rs868979094
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_000260.4(MYO7A):c.1117C>T(p.Arg373Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000351 in 1,425,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R373H) has been classified as Uncertain significance.
Frequency
Consequence
NM_000260.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.1117C>T | p.Arg373Cys | missense_variant | 11/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.1117C>T | p.Arg373Cys | missense_variant | 11/49 | 1 | NM_000260.4 | ||
MYO7A | ENST00000458637.6 | c.1117C>T | p.Arg373Cys | missense_variant | 11/49 | 1 | P1 | ||
MYO7A | ENST00000409619.6 | c.1084C>T | p.Arg362Cys | missense_variant | 12/50 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000351 AC: 5AN: 1425190Hom.: 0 Cov.: 31 AF XY: 0.00000425 AC XY: 3AN XY: 705470
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | research | King Laboratory, University of Washington | Aug 01, 2020 | MYO7A c.1117C>T, p.R373C alters a completely conserved residue of MYO7A in all sequenced vertebrates. The variant is homozygous in 8 Palestinian children from an extended kindred with severe to profound pre-lingual hearing loss (Abu Rayyan 2020). The variant is absent from 1300 Palestinian controls and absent from gnomAD v2.1.1. - |
Pathogenic, no assertion criteria provided | research | Hereditary Research Laboratory, Bethlehem University | Jun 04, 2016 | severe-profound - |
not provided Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 29, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 373 of the MYO7A protein (p.Arg373Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal recessive non-syndromic deafness (PMID: 22903915, 30733538, 32467589, 32747562). ClinVar contains an entry for this variant (Variation ID: 228997). 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. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | MYO7A: PM2, PP1, PP3 - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 18, 2015 | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg373Cys variant in MYO7A has been reported in 2 Iranian siblings with hearing loss, bot h of whom were homozygous for the variant (Babanejad 2012). Data from large popu lation studies is insufficient to assess the frequency of this variant; however, the variant was reportedly not identified in 200 Iranian chromosomes (Babanejad 2012). Computational prediction tools and conservation analysis suggest that th is variant may impact the protein, though this information is not predictive eno ugh to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg373Cys variant is uncerta in. - |
Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 28, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at