Total submissions: 31
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Hacettepe Pediatric Genetics Laboratory, |
RCV000017741 | SCV005439182 | pathogenic | Hypochondroplasia | 2024-12-24 | criteria provided, single submitter | clinical testing | The FGFR3 c.1620C>G variant (p.Asn540Lys) was classified as "pathogenic" according to the ACMG criteria 2019. This variant was assessed as deleterious according to the SIFT prediction program (score 0) and the Mutation Taster prediction program (score 1).The Asn540Lys variant in FGFR3 has been reported in a Turkish patient with Hypochondroplasia (https://doi.org/10.4274/jcrpe.787). In summary, the Asn540Lys variant meets our criteria to be classified as pathogenic. |
| Juno Genomics, |
RCV005411260 | SCV005417699 | pathogenic | Achondroplasia; Camptodactyly-tall stature-scoliosis-hearing loss syndrome; Cervical cancer; Crouzon syndrome-acanthosis nigricans syndrome; Muenke syndrome; Thanatophoric dysplasia type 1; Thanatophoric dysplasia, type 2; Malignant tumor of urinary bladder; Hypochondroplasia; Epidermal nevus; Severe achondroplasia-developmental delay-acanthosis nigricans syndrome; Colorectal cancer; Germ cell tumor of testis; Lacrimoauriculodentodigital syndrome 2 | criteria provided, single submitter | clinical testing | PM2_Supporting+PS4+PS2+PS3_Moderate+PS1 | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001332222 | SCV005381294 | pathogenic | Achondroplasia | 2024-08-07 | criteria provided, single submitter | clinical testing | Variant summary: FGFR3 c.1620C>G (p.Asn540Lys) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250610 control chromosomes (gnomAD). c.1620C>G has been reported in the literature in multiple individuals affected with Hypochondroplasia, in some cases as a de novo occurrence (e.g. Maddirevula_2018, Zhu_2022). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1619A>G, p.Asn540Ser), supporting the critical relevance of codon 540 to FGFR3 protein function. The following publications have been ascertained in the context of this evaluation (PMID: 29620724, 35726512). ClinVar contains an entry for this variant (Variation ID: 16338). Based on the evidence outlined above, the variant was classified as pathogenic. |
| MGZ Medical Genetics Center | RCV001332222 | SCV002581158 | pathogenic | Achondroplasia | 2022-07-27 | criteria provided, single submitter | clinical testing | |
| 3billion | RCV001332222 | SCV002572640 | pathogenic | Achondroplasia | 2023-12-19 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.69 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.76 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000016338 /PMID: 8589686) and different missense changes at the same codon (p.Asn540Asp, p.Asn540His, p.Asn540Ser, p.Asn540Thr / ClinVar ID: VCV000016344, VCV000016349, VCV000374828, VCV001325830 /PMID: 10777366, 9452043) have been previously reported as pathogenic/likely pathogenic with strong evidence.The variant has been observed in at least two similarly affected unrelated individuals (PMID: 25614871). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. |
| Genome Diagnostics Laboratory, |
RCV002276553 | SCV002566624 | pathogenic | Connective tissue disorder | 2020-07-01 | criteria provided, single submitter | clinical testing | |
| Laboratorio de Genetica e Diagnostico Molecular, |
RCV000017741 | SCV002512729 | pathogenic | Hypochondroplasia | 2021-12-30 | criteria provided, single submitter | clinical testing | ACMG classification criteria: PS1 strong, PS3 supporting, PS4 strong, PM2 moderate |
| Kasturba Medical College, |
RCV000017741 | SCV002507199 | likely pathogenic | Hypochondroplasia | 2022-05-09 | criteria provided, single submitter | clinical testing | |
| Kasturba Medical College, |
RCV001804740 | SCV002050695 | pathogenic | Larsen syndrome | 2021-12-25 | criteria provided, single submitter | clinical testing | |
| Blueprint Genetics | RCV000255372 | SCV001832469 | pathogenic | not provided | 2019-11-30 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV001332222 | SCV001524466 | pathogenic | Achondroplasia | 2020-02-14 | criteria provided, single submitter | clinical testing | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. |
| Ce |
RCV000255372 | SCV001500775 | pathogenic | not provided | 2022-05-01 | criteria provided, single submitter | clinical testing | FGFR3: PS4, PM2, PM6, PP3, PP4 |
| Clinical Genetics and Genomics, |
RCV000255372 | SCV001449926 | pathogenic | not provided | 2018-05-31 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV000763122 | SCV000893667 | pathogenic | Achondroplasia; Camptodactyly-tall stature-scoliosis-hearing loss syndrome; Cervical cancer; Crouzon syndrome-acanthosis nigricans syndrome; Levy-Hollister syndrome; Muenke syndrome; Thanatophoric dysplasia type 1; Thanatophoric dysplasia, type 2; Malignant tumor of urinary bladder; Hypochondroplasia; Epidermal nevus; Severe achondroplasia-developmental delay-acanthosis nigricans syndrome; Malignant tumor of testis; Carcinoma of colon | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| ARUP Laboratories, |
RCV000255372 | SCV000885457 | pathogenic | not provided | 2024-09-23 | criteria provided, single submitter | clinical testing | The FGFR3 c.1620C>G; p.Asn540Lys variant (rs28933068) is a recurrent alteration in patients with hypochondroplasia (Camera 2001, Kannu 2007, Korkmaz 2012, Linnankivi 2012, Xue 2014). Another variant at this position, c.1620C>A, also results in the same amino acid alteration (p.Asn540Lys), and is the most common pathogenic variant in hypochondroplasia patients (Xue 2014). Functional characterization of the variant protein indicates increased phosphorylation of ERK1/2, resulting in an over-activation of the MAPK signaling pathway (Krejci 2008). The c.1620C>G; p.Asn540Lys variant is reported in ClinVar (Variation ID: 16338). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, the p.Asn540Lys variant is considered to be pathogenic. References: Camera G et al. Occurrence of thanatophoric dysplasia type I (R248C) and hypochondroplasia (N540K) mutations in two patients with achondroplasia phenotype. Am J Med Genet. 2001; 104(4):277-81. PMID: 11754059. Kannu P et al. FGFR3 mutations and medial temporal lobe dysgenesis. J Child Neurol. 2007; 22(2):211-3. PMID: 17621485. Korkmaz HA et al. Hypochondroplasia in a child with 1620C>G (Asn540Lys) mutation in FGFR3. J Clin Res Pediatr Endocrinol. 2012; 4(4):220-2. PMID: 23149434. Krejci P et al. Analysis of STAT1 activation by six FGFR3 mutants associated with skeletal dysplasia undermines dominant role of STAT1 in FGFR3 signaling in cartilage. PLoS One. 2008; 3(12):e3961. PMID: 19088846. Linnankivi T et al. Neuroimaging and neurological findings in patients with hypochondroplasia and FGFR3 N540K mutation. Am J Med Genet A. 2012; 158A(12):3119-25. PMID: 23165795. Xue Y et al. FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry. Mol Genet Genomic Med. 2014; 2(6):497-503. PMID: 25614871. |
| Ambry Genetics | RCV000622950 | SCV000741814 | pathogenic | Inborn genetic diseases | 2016-09-19 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000255372 | SCV000640362 | pathogenic | not provided | 2025-01-18 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 540 of the FGFR3 protein (p.Asn540Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypochondroplasia or achondroplasia (PMID: 7670477, 8589686, 9452043, 10360392, 11055896, 11754059, 23149434, 23165795, 25614871). ClinVar contains an entry for this variant (Variation ID: 16338). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt FGFR3 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 19088846). For these reasons, this variant has been classified as Pathogenic. |
| Centre for Mendelian Genomics, |
RCV000415460 | SCV000492852 | pathogenic | Short stature | 2015-06-23 | criteria provided, single submitter | clinical testing | |
| Eurofins Ntd Llc |
RCV000255372 | SCV000341534 | pathogenic | not provided | 2018-04-05 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000255372 | SCV000321637 | pathogenic | not provided | 2022-08-17 | criteria provided, single submitter | clinical testing | Observed in multiple individuals with hypochondroplasia in the published literature (Prinos et al., 1995; Foldynova-Trantirkova et al., 2012); Published functional studies demonstrate this variant results in significantly reduced in vitro expression (Raffioni et al., 1998); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8640234, 29681095, 10360392, 22045636, 23149434, 9857065, 23165795, 11754059, 19088846, 8589686, 28777845, 29478821, 29150894, 17621485, 29620724, 30355600, 26380986, 34567078, 33942288, 32712949, 33389251) |
| Programa de Pós- |
RCV000017741 | SCV000223910 | pathogenic | Hypochondroplasia | 2015-04-01 | criteria provided, single submitter | research | |
| Prevention |
RCV004737156 | SCV005344551 | pathogenic | FGFR3-related disorder | 2024-08-26 | no assertion criteria provided | clinical testing | The FGFR3 c.1620C>G variant is predicted to result in the amino acid substitution p.Asn540Lys. This variant has been reported to be the most common cause of hypochondroplasia (Bellus et al. 1995. PubMed ID: 7670477; Prinos et al. 1995. PubMed ID: 8589686). Additionally, functional studies support its pathogenicity (Raffioni et al. 1998. PubMed ID: 9857065). This variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic. |
| Department of Pediatrics, |
RCV000017741 | SCV005045297 | pathogenic | Hypochondroplasia | 2024-02-01 | no assertion criteria provided | clinical testing | |
| Clinical Laboratory Sciences Program |
RCV000017741 | SCV003927827 | pathogenic | Hypochondroplasia | 2023-04-01 | no assertion criteria provided | clinical testing | |
| Laboratory of Diagnostic Genome Analysis, |
RCV000255372 | SCV002036285 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000255372 | SCV001964698 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000255372 | SCV001955913 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Bioscientia Institut fuer Medizinische Diagnostik Gmb |
RCV000017741 | SCV000746072 | pathogenic | Hypochondroplasia | 2017-09-18 | no assertion criteria provided | clinical testing | |
| Clinical Molecular Genetics Laboratory, |
RCV000017741 | SCV000692270 | pathogenic | Hypochondroplasia | 2016-04-06 | no assertion criteria provided | clinical testing | |
| Gene |
RCV000017741 | SCV000086722 | not provided | Hypochondroplasia | no assertion provided | literature only | Most common pathogenic variant in hypochondroplasia | |
| OMIM | RCV000017741 | SCV000038019 | pathogenic | Hypochondroplasia | 1999-04-01 | no assertion criteria provided | literature only |