Submissions for variant NM_000260.4(MYO7A):c.1849T>C (p.Ser617Pro)

dbSNP: rs782063761

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000504967	SCV001164263	uncertain significance	Usher syndrome	2019-08-26	reviewed by expert panel	curation	The p.Ser617Pro variant was present in 0.008716% (2/22946) of South Asian chromosomes in gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting; gnomad.broadinstitute.org). This variant has been reported in 1 South Asian proband with Usher syndrome (PP4; PMID: 28041643). This individual was compound heterozygous with a pathogenic variant (VCV000438178.1) which was assumed to be in trans (PM3_Supporting). Of note, this variant was observed in 2 additional probands; however, it was not specified whether or not these individuals presented with phenotypes other than hearing loss (PMID: 27344577, 30303587). Computational prediction tools and conservation analysis suggest that the p.Ser617Pro variant may impact the protein (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM3_Supporting, PP3, PP4.
Counsyl	RCV000670176	SCV000795003	uncertain significance	Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2017-10-24	criteria provided, single submitter	clinical testing
3billion	RCV000681537	SCV002521242	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MYO7A related disorder (ClinVar ID: VCV000438172 / PMID: 28041643). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 33187236) and co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 33187236). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Invitae	RCV003558426	SCV004294130	pathogenic	not provided	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 617 of the MYO7A protein (p.Ser617Pro). 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 missense change has been observed in individual(s) with autosomal recessive deafness, MYO7A-related conditions, and/or Usher syndrome type 1 (PMID: 28041643, 30303587, 33671976; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 438172). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504967	SCV000599114	likely pathogenic	Usher syndrome	2015-01-01	no assertion criteria provided	research
National Institute on Deafness and Communication Disorders, National Institutes of Health	RCV000681537	SCV000807729	pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2018-07-05	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291471	SCV001479975	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research