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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1175Q) has been classified 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.3523C>T | p.Arg1175Trp | missense_variant | 27/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.3523C>T | p.Arg1175Trp | missense_variant | 26/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.3523C>T | p.Arg1175Trp | missense_variant | 27/40 | 1 | NM_000257.4 | P1 |
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
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | Feb 23, 2018 | 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'. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 21, 2020 | This sequence change replaces arginine with tryptophan at codon 1175 of the MYH7 protein (p.Arg1175Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. In summary, this variant is a missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). The frequency data for this variant (rs566368210) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a MYH7-related disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at