Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001171536 | SCV001334321 | pathogenic | Pendred syndrome | 2020-02-19 | reviewed by expert panel | curation | The p.Val402Met variant in SLC26A4 was absent from gnomAD v2.1.1 and v3 (PM2). This variant has been detected in 2 probands with hearing loss. For both patients, a pathogenic or suspected-pathogenic variant was observed in trans (PM3_Strong, PMID:19204907, Partners LMM unpublished data SCV000060082.6). The variant has been reported to segregate in one affected family member (PP1, PMID:19204907). At least one proband with this variant displayed features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PP4, LMM unpublished data SCV000060082.6). Functional studies including fluorescence assays have demonstrated that this variant impacts protein function (PS3_Supporting; PMID:19204907). The REVEL computational prediction analysis tool produced a score of 0.77, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM3_Strong, PM2, PP1, PP3, PP4, PS3_Supporting). |
Laboratory for Molecular Medicine, |
RCV000036427 | SCV000060082 | likely pathogenic | Rare genetic deafness | 2016-11-17 | criteria provided, single submitter | clinical testing | The p.Val402Met variant in SLC26A4 has been identified in the compound heterozyg ous state with another pathogenic variant in SLC26A4 in two siblings with enlarg ed vestibular aqueduct (Choi 2009) and in an individual with hearing loss tested by our laboratory. This variant has not been reported in large population studi es. A study has shown that the p.Val402Met variant may impact protein function ( Choi 2009). In summary, although additional studies are required to fully establ ish its clinical significance, this variant is likely pathogenic. |
Gene |
RCV002272039 | SCV002558571 | pathogenic | not provided | 2022-01-26 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect due to loss of anion transporter activity of the variant protein (Choi BY et al., 2009); Reported as pathogenic by the ClinGen Hearing Loss Expert Panel but additional evidence is not available (ClinVar SCV001334321.1; Oza et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27771369, 20128824, 19204907, 30311386) |
Baylor Genetics | RCV003473262 | SCV004204223 | likely pathogenic | Autosomal recessive nonsyndromic hearing loss 4 | 2023-01-23 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001171536 | SCV005422309 | likely pathogenic | Pendred syndrome | 2024-10-14 | criteria provided, single submitter | clinical testing | Variant summary: SLC26A4 c.1204G>A (p.Val402Met) results in a conservative amino acid change located in the SLC26A/SulP transporter domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250984 control chromosomes. c.1204G>A has been reported in the literature in two compound heterozygous siblings affected with hearing loss and enlargement of the vestibular aqueduct (e.g., Choi_2009). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (e.g., Choi_2009, Takahashi_2024). The most pronounced variant effect results in <10% of normal anion transport function in a fluorometric antiport assay (e.g., Takahashi_2024). The following publications have been ascertained in the context of this evaluation (PMID: 19204907, 38474007). ClinVar contains an entry for this variant (Variation ID: 43495). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
Natera, |
RCV001171536 | SCV002079992 | likely pathogenic | Pendred syndrome | 2021-07-26 | no assertion criteria provided | clinical testing |