NM_002471.4:c.4036C>T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_002471.4(MYH6):c.4036C>T(p.Arg1346Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,202 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_002471.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.4036C>T | p.Arg1346Trp | missense_variant | Exon 29 of 39 | ENST00000405093.9 | NP_002462.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000658 AC: 10AN: 151984Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250728Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135564
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461218Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 726928
GnomAD4 genome AF: 0.0000658 AC: 10AN: 151984Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74212
ClinVar
Submissions by phenotype
not specified Uncertain:2
Variant summary: MYH6 c.4036C>T (p.Arg1346Trp) results in a non-conservative amino acid change located in the Myosin tail domain 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 1.6e-05 in 250728 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4036C>T has been reported in the literature in an individual affected with Cardiomyopathy (Tariq_2012). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
The Arg1346Trp variant in MYH6 has not been reported in the literature nor previ ously identified by our laboratory. This variant has been identified in 1/8600 E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS). Computational analyses (biochemic al amino acid properties, conservation, AlignGVGD, and SIFT) suggest that this v ariant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additional information is needed to fully assess the clinical significance of this variant. -
Hypertrophic cardiomyopathy 14 Uncertain:2
The missense c.4036C>T(p.Arg1346Trp) variant in MYH6 gene has been submitted to ClinVar as a Variant of Uncertain Significance. It has not been reported in affected individuals. The variant is observed in 0.002% alleles in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Arg at position 1346 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance. -
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1346 of the MYH6 protein (p.Arg1346Trp). This variant is present in population databases (rs372736126, gnomAD 0.008%). This missense change has been observed in individual(s) with MYH6-related congenital heart defects (PMID: 35456442). ClinVar contains an entry for this variant (Variation ID: 44502). 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 not expected to disrupt MYH6 protein function with a negative predictive value of 80%. 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. -
Cardiomyopathy Uncertain:1
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not provided Uncertain:1
Identified in the apparent homozygous state in an individual with DCM referred for genetic testing at GeneDx; 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: 34983622, 35456442) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at