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	RCV004595510	SCV001164263	likely pathogenic	Nonsyndromic genetic hearing loss	2024-06-28	reviewed by expert panel	curation	The c.1849T>C variant in MYO7A is a missense variant predicted to cause substitution of serine by proline at amino acid 617 (p.Ser617Pro). The highest population minor allele frequency in gnomAD v4 is 0.00009496 (8/84244 alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.922, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in 3 individuals with nonsyndromic hearing loss. Of those individuals, 2 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and both of those were confirmed in trans by parental testing (c.20G>T [p.Gly7Val], c.1258A>T [p.K420*], 2 PM3 points, PMIDs: 30303587, 33187236). One individual was homozygous for the variant (0.5 PM3 points, PMIDs: 27344577, 33671976) (PM3). The variant has been reported to segregate with nonsyndromic hearing loss in 7 affected family members from 3 families (PP1_Strong; PMIDs: 27344577, 30303587, 33187236, 33671976). This variant has also been detected in 1 individual with Usher syndrome, with a second variant c.4838delA (p.Asp1613ValfsTer32) without phase confirmation (PMIDs: 28041643, 32581362). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP1_S, PM3, PP3. (Hearing Loss VCEP specifications version 2; 4/22/2024). As cases have been observed with both nonsyndromic hearing loss and Usher syndrome and genotype-phenotype correlation is currently unclear, individuals should be evaluated for both conditions.
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.
Labcorp Genetics (formerly Invitae), Labcorp	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