Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001252670 | SCV001428429 | likely pathogenic | Usher syndrome | 2024-09-24 | reviewed by expert panel | curation | The c.5804T>C variant in MYO7A is a missense variant predicted to cause substitution of leucine by proline at amino acid 1935 (p.Leu1935Pro). The highest population minor allele frequency in gnomAD v4.1 is 0.00002204 (26/1179460 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (≤0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.961, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in 2 individuals with autosomal recessive Usher syndrome. Both were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and both of those were confirmed in trans by family testing (2 PM3 points, SCV001239772.1, SCV000059855.6, Blueprint Genetics, Laboratory for Molecular Medicine) (PM3_Strong). At least one patient with this variant displayed sensorineural hearing loss with retinitis pigmentosa, which is highly specific for autosomal recessive Usher syndrome (PP4, SCV000059855.6, Laboratory for Molecular Medicine). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_Strong, PM2_Supporting, PP3, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 9/24/2024) |
| Counsyl | RCV000675068 | SCV000800545 | uncertain significance | Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1 | 2017-06-02 | criteria provided, single submitter | clinical testing | |
| Blueprint Genetics | RCV001074201 | SCV001239772 | likely pathogenic | Retinal dystrophy | 2019-03-15 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV002513375 | SCV003002340 | uncertain significance | not provided | 2022-05-17 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1935 of the MYO7A protein (p.Leu1935Pro). This variant is present in population databases (rs397516323, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MYO7A-related conditions. ClinVar contains an entry for this variant (Variation ID: 43298). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYO7A protein function. 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. |
| Laboratory for Molecular Medicine, |
RCV000036203 | SCV000059855 | likely pathogenic | Rare genetic deafness | 2010-08-16 | no assertion criteria provided | clinical testing | The Leu1935Pro variant in MYO7A has not been reported in the literature. This re sidue is conserved across species and computational analyses (PolyPhen, SIFT) su ggest that the Leu1935Pro variant may impact the protein. This variant was detec ted in a patient in combination with a reported pathogenic variant increasing th e likelihood that the Leu1935Pro variant is pathogenic. In summary, this variant is likely to be pathogenic. |