rs1555067667
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000260.4(MYO7A):c.1190C>A(p.Ala397Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000256 in 1,563,768 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. A397T) has been classified as Likely pathogenic.
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.1190C>A | p.Ala397Asp | missense_variant | 11/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.1190C>A | p.Ala397Asp | missense_variant | 11/49 | 1 | NM_000260.4 | ||
MYO7A | ENST00000458637.6 | c.1190C>A | p.Ala397Asp | missense_variant | 11/49 | 1 | P1 | ||
MYO7A | ENST00000409619.6 | c.1157C>A | p.Ala386Asp | missense_variant | 12/50 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152190Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000142 AC: 2AN: 1411578Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1AN XY: 697616
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74340
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 397 of the MYO7A protein (p.Ala397Asp). This variant is present in population databases (no rsID available, gnomAD no frequency). This missense change has been observed in individuals with Usher syndrome (PMID: 9382091, 20497194). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 553245). 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%. Experimental studies have shown that this missense change affects MYO7A function (PMID: 18700726). This variant disrupts the p.Ala397 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23591405, 28944237; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 06, 2024 | Published functional studies demonstrate a damaging effect with severe dysfunction of the myosin VIIa motor function (PMID: 18700726); 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: 12786748, 9703432, 9382091, 23148716, 31589614, 33576163, 32991204, 35076463, 18700726, 30459346, 31130284, 16470552) - |
Usher syndrome type 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 10, 2021 | NM_000260.3(MYO7A):c.1190C>A(A397D) is a missense variant classified as likely pathogenic in the context of MYO7A-related disorders. A397D has been observed in cases with relevant disease (PMID: 9382091, 16470552, 23148716, 30459346). Functional assessments of this variant are available in the literature (PMID: 18700726). A397D has been observed in population frequency databases (gnomAD: OTH 0.09%). In summary, NM_000260.3(MYO7A):c.1190C>A(A397D) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 13, 2021 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Dec 21, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at