rs201051663
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_002471.4(MYH6):c.3758C>T(p.Thr1253Met) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,614,032 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.3758C>T | p.Thr1253Met | missense_variant | Exon 27 of 39 | ENST00000405093.9 | NP_002462.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251458Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135914
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461892Hom.: 0 Cov.: 33 AF XY: 0.0000261 AC XY: 19AN XY: 727248
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Benign. The p.Thr1253Met va riant in MHY6 has not been previously reported in individuals with cardiomyopath y or in large population studies. Threonine (Thr) at position 1253 is not conser ved in mammals or in evolutionarily distant species and 2 mammals (macaque and m anatee) have a methionine (Met) at this position, suggesting that this change ma y be tolerated. Additional computational prediction tools suggest that the p.Thr 1253Met variant may impact the protein, though this information is not predictiv e enough to determine pathogenicity. In summary, while the clinical significance of the p.Thr1253Met variant is uncertain, the presence of the variant amino aci d in other mammals suggests that it is more likely to be benign. -
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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not provided Uncertain:1
The T1253M variant in the MYH6 gene has been reported previously in an individual with sporadic dilated cardiomyopathy (Zhao et al., 2015). The T1253M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T1253M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T1253M as a variant of uncertain significance. -
MYH6-related disorder Uncertain:1
The MYH6 c.3758C>T variant is predicted to result in the amino acid substitution p.Thr1253Met. This variant was reported in an individual with dilated cardiomyopathy (Zhao et al. 2015. PubMed ID: 26458567) and an individual with left ventricular noncompaction (Table S2, Mazzarotto et al. 2021. PubMed ID: 33500567). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD and has been interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/164229/). 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.T1253M variant (also known as c.3758C>T), located in coding exon 25 of the MYH6 gene, results from a C to T substitution at nucleotide position 3758. The threonine at codon 1253 is replaced by methionine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at