rs202120238
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2PP3_ModerateBS2
The NM_002471.4(MYH6):c.2383C>T(p.Arg795Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,614,090 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. R795Q) has been classified 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 -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.2383C>T | p.Arg795Trp | missense_variant | 20/39 | ENST00000405093.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH6 | ENST00000405093.9 | c.2383C>T | p.Arg795Trp | missense_variant | 20/39 | 5 | NM_002471.4 | P1 | |
ENST00000702194.1 | upstream_gene_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000138 AC: 21AN: 152172Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000995 AC: 25AN: 251340Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135858
GnomAD4 exome AF: 0.000162 AC: 237AN: 1461800Hom.: 0 Cov.: 32 AF XY: 0.000149 AC XY: 108AN XY: 727190
GnomAD4 genome ? AF: 0.000138 AC: 21AN: 152290Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74466
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 26, 2022 | Variant summary: MYH6 c.2383C>T (p.Arg795Trp) results in a non-conservative amino acid change in 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 9.9e-05 in 251340 control chromosomes, predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. c.2383C>T has been reported in the literature in an individual affected with hypoplastic left heart syndrome and in a survivor of sudden cardiac arrest due to exercise-related mitral valve prolapse (e.g. Tomita-Mitchell_2016, Asatryan_2019). These reports do not provide unequivocal conclusions about association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Hypertrophic cardiomyopathy 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 07, 2023 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 470512). This missense change has been observed in individual(s) with MYH6-related conditions (PMID: 27789736, 28082330, 30975432). This variant is present in population databases (rs202120238, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 795 of the MYH6 protein (p.Arg795Trp). - |
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
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 07, 2021 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Aug 02, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 14, 2021 | Reported in a proband with hypoplastic left heart syndrome (Tomita-Mitchell et al., 2016) and in a proband with mitral valve prolapse and a history of sudden cardiac arrest in the published literature (Asatryan et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 470512; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30975432, 27789736) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 03, 2023 | The p.R795W variant (also known as c.2383C>T), located in coding exon 18 of the MYH6 gene, results from a C to T substitution at nucleotide position 2383. The arginine at codon 795 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in a hypoplastic left heart syndrome cohort, but clinical details were limited (Tomita-Mitchell A et al. Physiol. Genomics, 2016 12;48:912-921). This alteration has also been reported in a sudden cardiac arrest cohort (Asatryan B et al. Am J Cardiol, 2019 06;123:2031-2038). This amino acid position is highly 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