rs367663906
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The NM_002471.4(MYH6):c.1628A>G(p.Lys543Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,992 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 (★★). Synonymous variant affecting the same amino acid position (i.e. K543K) 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 -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.1628A>G | p.Lys543Arg | missense_variant | 15/39 | ENST00000405093.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH6 | ENST00000405093.9 | c.1628A>G | p.Lys543Arg | missense_variant | 15/39 | 5 | NM_002471.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152100Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251030Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135718
GnomAD4 exome AF: 0.0000458 AC: 67AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.0000481 AC XY: 35AN XY: 727248
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152100Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5AN XY: 74318
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 06, 2020 | Reported previously in a family with atrial septal defects (Posch et al., 2011); Identified in a cohort of DCM patients (Dal Ferro et al., 2017) and was identified in a patient with LVNC who also harbored other cardiogenetic variants (Miszalski et al., 2017); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 228888; Landrum et al., 2016); 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: 30847666, 28798025, 28416588, 26014430, 22194935) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 03, 2015 | The p.Lys543Arg variant in MYH6 has been reported in one individual with atriove ntricular septal defect (AVSD) and segregated with disease in one affected relat ive. Two additional relatives also carried this variant; however these individua ls were unavailable for clinical evaluation (Posch 2011). In addition, this vari ant has been identified in 6/66734 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs367663906). Computati onal prediction tools and conservation analysis do not provide strong support fo r or against an impact to the protein. In summary, the clinical significance of the p.Lys543Arg variant is uncertain. - |
Hypertrophic cardiomyopathy 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 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 not expected to disrupt MYH6 protein function. ClinVar contains an entry for this variant (Variation ID: 228888). This missense change has been observed in individual(s) with MYH6-related conditions (PMID: 22194935, 28416588, 28798025, 30847666). This variant is present in population databases (rs367663906, gnomAD 0.01%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 543 of the MYH6 protein (p.Lys543Arg). - |
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 15, 2021 | - - |
MYH6-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 12, 2024 | The MYH6 c.1628A>G variant is predicted to result in the amino acid substitution p.Lys543Arg. This variant has been reported in a family with atrial septal defects (Posch et al. 2011. PubMed ID: 22194935) and in patients with dilated cardiomyopathy, hypertrophic cardiomyopathy, or left ventricular noncompaction (Table S1, Dal Ferro et al. 2017. PubMed ID: 28416588; Table S3, Miszalski-Jamka et al. 2017. PubMed ID: 28798025; Table S2, van Lint et al. 2019. PubMed ID: 30847666). This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD. 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
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 04, 2021 | The p.K543R variant (also known as c.1628A>G), located in coding exon 13 of the MYH6 gene, results from an A to G substitution at nucleotide position 1628. The lysine at codon 543 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in affected and unaffected family members in a family with atrial septal defect (Posch MG et al. PLoS One, 2011 Dec;6:e28872). This variant was detected in a cardiomyopathy genetic testing cohort and in a subject with left ventricular non-compaction (LVNC); however, clinical details were limited, and additional cardiac variants were detected in some cases (Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10:; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). 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