Submissions for variant NM_000260.4(MYO7A):c.5345G>C (p.Gly1782Ala)

dbSNP: rs751242455

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genome-Nilou Lab	RCV001580535	SCV001810515	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2021-07-22	criteria provided, single submitter	clinical testing
Invitae	RCV001861875	SCV002314260	likely pathogenic	not provided	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1782 of the MYO7A protein (p.Gly1782Ala). This variant is present in population databases (rs751242455, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal recessive MYO7A-related disorders (PMID: 30303587). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 560898). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323681	SCV004030129	uncertain significance	not specified	2023-07-06	criteria provided, single submitter	clinical testing	Variant summary: MYO7A c.5345G>C (p.Gly1782Ala) results in a non-conservative amino acid change located in the MyTH4 domain (IPR000857) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 227376 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYO7A causing Usher Syndrome (4.4e-05 vs 0.0061), allowing no conclusion about variant significance. c.5345G>C has been reported in the literature in individuals affected with hearing loss, however also observed in their unaffected siblings and mother (Richard_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30303587). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Center for Statistical Genetics, Columbia University	RCV000679825	SCV000804816	pathogenic	Deafness	2018-09-10	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291101	SCV001479467	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research