rs373629059
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_002471.4(MYH6):āc.5519A>Gā(p.Lys1840Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,612,794 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. K1840K) has been classified as Likely benign.
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.5519A>G | p.Lys1840Arg | missense_variant | 36/39 | ENST00000405093.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH6 | ENST00000405093.9 | c.5519A>G | p.Lys1840Arg | missense_variant | 36/39 | 5 | NM_002471.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000112 AC: 17AN: 152252Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000558 AC: 14AN: 250862Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135656
GnomAD4 exome AF: 0.000108 AC: 158AN: 1460542Hom.: 0 Cov.: 34 AF XY: 0.000117 AC XY: 85AN XY: 726596
GnomAD4 genome ? AF: 0.000112 AC: 17AN: 152252Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7AN XY: 74378
ClinVar
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 23, 2020 | Reported in one individual with late-onset hypertrophic cardiomyopathy and one individual with hypoplastic left heart syndrome (Rubattu et al., 2016; Tomita-Mitchell et al., 2016); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 264214; Landrum et al., 2016); At the protein level, in silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; At the mRNA level, in-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing; in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 27483260, 27789736, 30847666, 32880476) - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 14, 2022 | Variant summary: MYH6 c.5519A>G (p.Lys1840Arg) results in a conservative amino acid change located in the Myosin tail (IPR002928) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250862 control chromosomes. The observed variant frequency is approximately 2.23 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant is benign. c.5519A>G has been reported in the literature in individuals affected with Cardiomyopathy and Hypoplastic left heart syndrome without evidence of causality (e.g. Tomita-Mitchell_2016, Rubattu_2016, Preveden_2022). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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 uncertain significance. - |
Hypertrophic cardiomyopathy 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 17, 2023 | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1840 of the MYH6 protein (p.Lys1840Arg). This variant is present in population databases (rs373629059, gnomAD 0.01%). This missense change has been observed in individual(s) with MYH6-related conditions (PMID: 27483260, 27789736, 30847666, 32880476). ClinVar contains an entry for this variant (Variation ID: 264214). 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. 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
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 30, 2021 | - - |
Dilated cardiomyopathy 1EE Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 11, 2023 | The p.K1840R variant (also known as c.5519A>G), located in coding exon 34 of the MYH6 gene, results from an A to G substitution at nucleotide position 5519. The lysine at codon 1840 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy cohorts, in a dilated cardiomyopathy cohort, and in a hypoplastic left heart syndrome cohort; however, clinical details were limited (Rubattu S et al. Int J Mol Sci. 2016;17; Tomita-Mitchell A et al. Physiol. Genomics. 2016;48:912-921; Mazzarotto F et al. Genet Med, 2019 02;21:284-292; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 10;13:476-487). 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. - |
Left ventricular noncompaction 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Jan 04, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at