chr14-23386019-C-T
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_002471.4(MYH6):c.5072G>A(p.Arg1691His) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,614,210 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. R1691C) has been classified as Uncertain significance.
Frequency
Consequence
NM_002471.4 missense
Scores
Clinical Significance
Conservation
Publications
- hypertrophic cardiomyopathy 14Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
- Keppen-Lubinsky syndromeInheritance: AD Classification: MODERATE Submitted by: Illumina
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- atrial septal defect 3Inheritance: AD Classification: LIMITED Submitted by: G2P
- dilated cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
- hypertrophic cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.5072G>A | p.Arg1691His | missense_variant | Exon 34 of 39 | ENST00000405093.9 | NP_002462.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.0000159 AC: 4AN: 251320 AF XY: 0.00000736 show subpopulations
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461876Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 727246 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152334Hom.: 0 Cov.: 31 AF XY: 0.0000268 AC XY: 2AN XY: 74504 show subpopulations
ClinVar
Submissions by phenotype
not provided Uncertain:2
Reported in association with cardiomyopathy in published literature; however, no segregation or functional studies were described (PMID: 28082330, 25351510, 31513939); Not observed at significant frequency in large population cohorts (gnomAD); 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: 25351510, 31513939, 38540378, 28082330) -
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not specified Uncertain:1
The Arg1691His variant in MYH6 has not been reported in the literature nor previ ously identified by our laboratory. This variant has not been identified in larg e European American and African American populations by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS), though it may be present in other populations. Computational analyses (biochemical amino acid properties, conserv ation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or agai nst an impact to the protein. At this time, additional studies are needed to ful ly assess the clinical significance of this variant. -
Hypertrophic cardiomyopathy 14 Uncertain:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1691 of the MYH6 protein (p.Arg1691His). This variant is present in population databases (rs727504502, gnomAD 0.006%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 31513939). ClinVar contains an entry for this variant (Variation ID: 178868). 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. -
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.5072G>A variant is predicted to result in the amino acid substitution p.Arg1691His. This variant has been reported in individuals with hypertrophic cardiomyopathy (Table S1, Lopes et al. 2015. PubMed ID: 25351510; Table S7, Walsh et al. 2017. PubMed ID: 28082330; Table S2, Robyns et al. 2020. PubMed ID: 31513939). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD and is interpreted as uncertain significance by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/178868/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hypertrophic cardiomyopathy Uncertain:1
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Cardiovascular phenotype Uncertain:1
The p.R1691H variant (also known as c.5072G>A), located in coding exon 32 of the MYH6 gene, results from a G to A substitution at nucleotide position 5072. The arginine at codon 1691 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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