rs199897298
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000260.4(MYO7A):c.3476G>T(p.Gly1159Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000405 in 1,599,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1159S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000260.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.3476G>T | p.Gly1159Val | missense_variant | 27/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.3476G>T | p.Gly1159Val | missense_variant | 27/49 | 1 | NM_000260.4 |
Frequencies
GnomAD3 genomes ? AF: 0.000210 AC: 32AN: 152264Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000219 AC: 49AN: 224146Hom.: 0 AF XY: 0.000222 AC XY: 27AN XY: 121436
GnomAD4 exome AF: 0.000426 AC: 616AN: 1447080Hom.: 0 Cov.: 31 AF XY: 0.000422 AC XY: 303AN XY: 718382
GnomAD4 genome ? AF: 0.000210 AC: 32AN: 152264Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74398
ClinVar
Submissions by phenotype
not provided Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1159 of the MYO7A protein (p.Gly1159Val). This variant is present in population databases (rs199897298, gnomAD 0.05%). This missense change has been observed in individual(s) with autosomal recessive nonsyndromic deafness or Usher syndrome (PMID: 21436283, 23208854, 26969326, 27068579). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1019G>T (p.Gly340Val). ClinVar contains an entry for this variant (Variation ID: 43206). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 09, 2017 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | MYO7A: PM3:Strong, PM1, PM2, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 02, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26486028, 31589614, 26969326, 23208854, 27068579, 21436283, 30245029, 27160483, 32795431) - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jan 04, 2017 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 30, 2023 | - - |
Hearing loss Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Aug 15, 2019 | - - |
Usher syndrome type 1B Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
MYO7A-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 01, 2024 | Variant summary: MYO7A c.3476G>T (p.Gly1159Val) 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 0.00022 in 224146 control chromosomes, allowing no conclusion about variant significance. c.3476G>T has been reported in the literature in the compound heterozygous state in multiple individuals affected with autosomal recessive non-syndromic hearing loss (e.g. Roux_2011, Schrauwen_2013, Sloan-Heggen_2016, Sommen_2016, Zazo-Seco_2017, van Beeck Calkoen_2019) and in at least one compound heterozygous individual with retinitis pigmentosa (Georgiou_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32795431, 21436283, 23208854, 26969326, 27068579, 28000701, 31152317). ClinVar contains an entry for this variant (Variation ID: 43206). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 17, 2021 | - - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 13, 2016 | The p.Gly1159Val variant in MYO7A has been reported in 9 individuals with hearin g loss (Roux 2011, Schrauwen 2013, LMM data). Four of these individuals were co mpound heterozygous with a second pathogenic or likely pathogenic MYO7A variant, with no indication of retinitis pigmentosa associated with Usher syndrome. Anot her with retinitis pigmentosa had a second variant of uncertain significance in MYO7A. This individual also reportedly has LCHAD, which may explain the retiniti s pigmentosa. This variant has been identified in 12/30732 (0.04%) of European c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs199897298); however, this frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conserva tion analysis suggest that this variant may impact the protein, though this info rmation is not predictive enough to determine pathogenicity. In summary, althoug h additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive hearing loss. However, it cannot be determined whether this variant causes type 1 Usher syndrome, atyp ical Usher syndrome, or nonsyndromic hearing loss without additional information . - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 01, 2024 | Variant summary: PALB2 c.3476G>T (p.Trp1159Leu) results in a non-conservative amino acid change located in the WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251480 control chromosomes (gnomAD v2.1, Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3476G>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function and found no damaging effect of this variant on homologous recombination or in a PARP inhibitor sensitivity assay (e.g., Boonen_2019). The following publication was ascertained in the context of this evaluation (PMID: 31757951). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Retinal dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Sep 04, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at