Total submissions: 13
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Department of Human Genetics, |
RCV001808425 | SCV007540760 | pathogenic | Autosomal dominant nonsyndromic hearing loss 5 | 2022-02-03 | criteria provided, single submitter | clinical testing | |
| Genetics Laboratory, |
RCV006250169 | SCV007097463 | pathogenic | Monogenic hearing loss | 2025-09-09 | criteria provided, single submitter | clinical testing | PS4_moderate, PS3_strong, PP1_strong |
| Juno Genomics, |
RCV001808425 | SCV005416637 | pathogenic | Autosomal dominant nonsyndromic hearing loss 5 | criteria provided, single submitter | clinical testing | Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. | |
| Labcorp Genetics |
RCV001092560 | SCV004294458 | pathogenic | not provided | 2025-02-13 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 7 of the DFNA5 gene. It does not directly change the encoded amino acid sequence of the DFNA5 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individuals with non-syndromic deafness (PMID: 14559215, 29266521). It has also been observed to segregate with disease in related individuals. Studies have shown that this variant results in skipping of exon 8 and introduces a new termination codon (PMID: 14559215). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. |
| Revvity Omics, |
RCV001808425 | SCV003826981 | pathogenic | Autosomal dominant nonsyndromic hearing loss 5 | 2022-02-02 | criteria provided, single submitter | clinical testing | |
| 3billion | RCV001808425 | SCV002318560 | pathogenic | Autosomal dominant nonsyndromic hearing loss 5 | 2022-03-22 | criteria provided, single submitter | clinical testing | The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 24506266, 19911014, 14559215) and reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 19911014, 14559215). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000179997, PMID:14559215). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000041). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. |
| King Laboratory, |
RCV001808425 | SCV002059892 | pathogenic | Autosomal dominant nonsyndromic hearing loss 5 | 2020-08-01 | criteria provided, single submitter | research | Analysis of patient-derived RNA indicates that DFNA5/GSDME c.991-15_991-13delTTC weakens exon 8 splice acceptor, leading to loss of exon 8 in message and stop at codon 372 (Abu Rayyan 2020). The variant is heterozygous in 5 Palestinian children with progressive hearing loss, with average age at onset of 17 years. It is absent from 1300 Palestinian controls and from gnomAD v2.1.1. |
| Institute of Medical Genetics and Applied Genomics, |
RCV001092560 | SCV001905592 | pathogenic | not provided | 2021-09-15 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV001092560 | SCV001768211 | pathogenic | not provided | 2026-03-23 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests that this variant does not alter splicing; Published functional studies demonstrate adjacent exon 8 skipping and describe a hypothesized dominant-negative mechanism (PMID: 14559215); This variant is associated with the following publications: (PMID: 14676472, 9771715, 17868390, 29266521, 29849037, 39066985, 41020988, 34956325, 19911014, 24506266, 14559215, 32486382, 38297846, 32747562, 36350814, 38400873, 35982127) |
| Ce |
RCV001092560 | SCV001249116 | pathogenic | not provided | 2020-10-01 | criteria provided, single submitter | clinical testing | |
| Laboratory for Molecular Medicine, |
RCV000156800 | SCV000206521 | pathogenic | Rare genetic deafness | 2014-10-03 | criteria provided, single submitter | clinical testing | c.991-21TTC[2] (DFNA5; NM_004403.2; Chr7g.24746008_24746010delGAA; GRCh37): The c.991-21TTC[2] variant in DFNA5 has been reported in 4 Asian individuals with no n-syndromic sensorineural hearing loss, segregated with disease in 27 affected r elatives from 3 families and was absent in 440 Asian control chromosomes (Yu 200 3, Park 2010, Nisho 2014). It has also been previously identified by our laborat ory in one individual with hearing loss. This variant is a deletion of one unit of a trinucleotide (TTC) repeat sequence normally present as a triplicate (3 rep eat units), resulting in two copies of the TTC repeat. This variant is located i n the 3' splice region and has been shown to cause aberrant splicing, by skippin g of exon 8 (Yu 2003), which is predicted to lead to an abnormal or absent prote in. Several other variants in DFNA5 that have been reported to cause hearing los s are located in introns 7 or 8 and are expected to cause exon 8 skipping (Bisch off 2004, Van Laer 2005, Cheng 2007). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hearing loss based on the pr evious reports in affected individuals, segregations, and absence in controls. |
| Diagnostics Centre, |
RCV001808425 | SCV005049566 | pathogenic | Autosomal dominant nonsyndromic hearing loss 5 | 2023-10-24 | no assertion criteria provided | clinical testing | The GSDME:c.991-15_991-13delTTC splice variant is located 13 nucleotides upstream of exon 7 of the GSDME gene. This variant is classified as very rare in the overall population (allele frequency in gnomAD, v4.1.0= 0.000004114). The variant has been consistently classified as Pathogenic in nine entries in ClinVar (ClinVarID: 179997). The variant has been reported in several affected individuals with sensorineural with hearing loss and to co-segregate with the disease (PMID: 24506266, 19911014, 14559215). Experimental data suggest that the variant leads to skipping of exon 8 and thus to a non-functional protein (PMID: 14559215). In summary, this variant is classified as Pathogenic. |
| OMIM | RCV001808425 | SCV000022330 | pathogenic | Autosomal dominant nonsyndromic hearing loss 5 | 2010-01-01 | no assertion criteria provided | literature only |