rs566368210
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2PP3_Moderate
The NM_000257.4(MYH7):c.3523C>T(p.Arg1175Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000696 in 1,579,886 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 Uncertain significance (★★).
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151686Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000233 AC: 5AN: 214750Hom.: 0 AF XY: 0.0000255 AC XY: 3AN XY: 117474
GnomAD4 exome AF: 0.00000700 AC: 10AN: 1428082Hom.: 0 Cov.: 34 AF XY: 0.00000988 AC XY: 7AN XY: 708240
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151804Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74166
ClinVar
Submissions by phenotype
Sudden unexplained death Uncertain:1
MYH7 Arg1175Trp has been previously reported in a childhood myopathy case (Invitae, Pers. Comm.). We identified this variant in a HCM proband with a family history of HCM (segregation not possible). The variant is present at a low frequency in the Genome Aggregation Database (MAF= 0.00002, http://gnomad.broadinstitute.org/). In silico prediction tools SIFT, PolyPhen-HCM and MutationTaster predict this variant to be deleterious. In summary, based rarity in the general population and in silico tools predicting a deleterious affect we classify MYH7 Arg1175Trp as a variant of 'uncertain significance'. -
Hypertrophic cardiomyopathy Uncertain:1
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1175 of the MYH7 protein (p.Arg1175Trp). This variant is present in population databases (rs566368210, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 32894683). ClinVar contains an entry for this variant (Variation ID: 454367). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at