14-23384549-G-A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_002471.4(MYH6):c.5458C>T(p.Arg1820Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,486 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.5458C>T | p.Arg1820Trp | missense_variant | Exon 36 of 39 | ENST00000405093.9 | NP_002462.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000177 AC: 27AN: 152248Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251430Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135904
GnomAD4 exome AF: 0.0000260 AC: 38AN: 1461120Hom.: 0 Cov.: 34 AF XY: 0.0000234 AC XY: 17AN XY: 726856
GnomAD4 genome AF: 0.000184 AC: 28AN: 152366Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74508
ClinVar
Submissions by phenotype
not provided Uncertain:4
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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: 31983221, 32746448) -
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not specified Uncertain:1
The p.Arg1820Trp variant in MYH6 has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.1% (8/10400) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs111473291). Computational prediction tools and conservation analysis s uggest that the variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. In summary, the clinical significan ce of the p.Arg1820Trp variant is uncertain. -
Hypertrophic cardiomyopathy 14 Uncertain:1
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1820 of the MYH6 protein (p.Arg1820Trp). This variant is present in population databases (rs111473291, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32746448). ClinVar contains an entry for this variant (Variation ID: 228897). 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 MYH6 protein function with a positive 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. -
Dilated cardiomyopathy 1EE;C2750467:Hypertrophic cardiomyopathy 14;C3279790:Atrial septal defect 3;C3279791:Sick sinus syndrome 3, susceptibility to;C3495498:Hypertrophic cardiomyopathy 1 Uncertain:1
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MYH6-related disorder Uncertain:1
The MYH6 c.5458C>T variant is predicted to result in the amino acid substitution p.Arg1820Trp. This variant was reported as uncertain significance in an individual with dilated cardiomyopathy (Table S2, Burstein et al. 2021. PubMed ID: 32746448). This variant is reported in 0.072% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-23853758-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Cardiovascular phenotype Uncertain:1
The p.R1820W variant (also known as c.5458C>T), located in coding exon 34 of the MYH6 gene, results from a C to T substitution at nucleotide position 5458. The arginine at codon 1820 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort; however, clinical details were limited (Burstein DS et al. Pediatr Res, 2021 05;89:1470-1476). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at