Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000156720 | SCV000206441 | uncertain significance | not specified | 2014-08-11 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Pathogenic. The Arg124Trp v ariant in ATP6V1B1 has been reported in two individuals with distal renal tubula r acidosis (Karet 1999), and was absent from large population studies. These in dividuals were both homozygous for this variant and the variant segregated in an affected sibling of one of these individuals. Of note, neither individual were reported to have hearing loss, however they were under one year of age. Function in vitro studies have shown that the Arg124Trp variant impacts protein function (Fuster 2008, Yang 2006); however, these in vitro assays may not accurately rep resent biological function. Computational prediction tools and conservation anal yses suggest that the Arg124Trp variant may impact the protein, though this info rmation is not predictive enough to determine pathogenicity. In summary, while t here is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. |
| Department of Otolaryngology – Head & Neck Surgery, |
RCV001375115 | SCV001572028 | uncertain significance | Hearing impairment | 2021-04-12 | criteria provided, single submitter | clinical testing | PM2_Moderate, PP3_Supporting |
| Invitae | RCV002515034 | SCV003524615 | pathogenic | not provided | 2023-12-31 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 124 of the ATP6V1B1 protein (p.Arg124Trp). This variant is present in population databases (rs727505222, gnomAD 0.03%). This missense change has been observed in individual(s) with renal tubular acidosis (PMID: 9916796, 34159584). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 179919). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ATP6V1B1 function (PMID: 16769747, 18368028). For these reasons, this variant has been classified as Pathogenic. |