Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| All of Us Research Program, |
RCV000634709 | SCV004830661 | uncertain significance | Ehlers-Danlos syndrome, type 4 | 2024-05-30 | criteria provided, single submitter | clinical testing | This missense variant replaces asparagine with aspartic acid at codon 76 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with lacunar stroke (PMID: 31719132). This variant has been identified in 19/282052 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Gene |
RCV001570822 | SCV001795179 | uncertain significance | not provided | 2024-07-03 | criteria provided, single submitter | clinical testing | Reported in an individual with younger-onset small vessel disease (PMID: 31719132); In silico analysis indicates that this missense variant does not alter protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD); This variant is associated with the following publications: (PMID: 38944978, 31719132) |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001251398 | SCV001426984 | uncertain significance | not specified | 2025-05-23 | criteria provided, single submitter | clinical testing | Variant summary: COL3A1 c.226A>G (p.Asn76Asp) results in a conservative amino acid change located in the von Willebrand factor (vWF) type C domain (IPR001007) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00014 in 1606112 control chromosomes, predominantly at a frequency of 0.00018 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 120-fold of the estimated maximal expected allele frequency for a pathogenic variant in COL3A1 causing Ehlers-Danlos Syndrome, Vascular Type phenotype (1.5e-06). The variant, c.226A>G, has been observed in heterozygous state in at least two individuals diagnosed with Ehlers-Danlos Syndrome, Vascular Type (Manhas_2024), however no further details on these cases were provided. In addition, the variant has also been reported in an individual affected with lacunar stroke (Tan_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31719132, 38944978). ClinVar contains an entry for this variant (Variation ID: 519601). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. |
| Color Diagnostics, |
RCV001180581 | SCV001345540 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2024-02-07 | criteria provided, single submitter | clinical testing | This missense variant replaces asparagine with aspartic acid at codon 76 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with lacunar stroke (PMID: 31719132). This variant has been identified in 19/282052 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Illumina Laboratory Services, |
RCV000634709 | SCV001298980 | benign | Ehlers-Danlos syndrome, type 4 | 2018-01-12 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. |
| Labcorp Genetics |
RCV000634709 | SCV000756044 | uncertain significance | Ehlers-Danlos syndrome, type 4 | 2024-09-23 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 76 of the COL3A1 protein (p.Asn76Asp). This variant is present in population databases (rs142045411, gnomAD 0.01%). This missense change has been observed in individual(s) with lacunar stroke (PMID: 31719132). ClinVar contains an entry for this variant (Variation ID: 519601). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt COL3A1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Ambry Genetics | RCV001180581 | SCV000738525 | benign | Familial thoracic aortic aneurysm and aortic dissection | 2024-04-11 | criteria provided, single submitter | clinical testing | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |