rs199936506
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP6BS2
The NM_002471.4(MYH6):c.4505G>A(p.Arg1502Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1502W) 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 -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.4505G>A | p.Arg1502Gln | missense_variant | 31/39 | ENST00000405093.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH6 | ENST00000405093.9 | c.4505G>A | p.Arg1502Gln | missense_variant | 31/39 | 5 | NM_002471.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000217 AC: 33AN: 152040Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000171 AC: 43AN: 251440Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135890
GnomAD4 exome AF: 0.000171 AC: 250AN: 1461894Hom.: 0 Cov.: 37 AF XY: 0.000162 AC XY: 118AN XY: 727248
GnomAD4 genome ? AF: 0.000217 AC: 33AN: 152040Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74258
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 12, 2023 | Reported with the I275N variant in the MYH6 gene in two individuals with DCM; one individual also harbored a pathogenic variant in the TNNT2 gene (Hershberger et al., 2010; Rampersaud et al., 2011), and one individual harbored a third missense variant in the MYH6 gene (Carniel et al., 2005); Also reported in two individuals with HCM (Lopes et al., 2015), one individual with Ebstein's anomaly who also harbored two candidate copy number variants (Sicko et al., 2016), and in one individual from the ClinSeq cohort of individuals who underwent exome sequencing but were not selected for a history of cardiomyopathy, arrhythmia or family history of sudden cardiac death, although additional clinical details were not described (Ng et al., 2013); 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: 23861362, 23299917, 20215591, 22337857, 21483645, 25351510, 27788187, 15998695, 32789579, AlMutairi2020[Publication]) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2023 | MYH6: BS1 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 26, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 20, 2012 | Variant classified as Uncertain Significance - Favor Benign. The Arg1502Gln vari ant (MYH6) was reported in two individuals with DCM and was absent from at least 792 control chromosomes (Carniel 2005, Hershberger 2010). One of these individ uals also carried a pathogenic DCM variant as well as a second variant in MYH6 ( Ile275Asn). The variant was present in 0.05% (3/7020) of European American chro mosomes from a broad population by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu/EVS/); however, this frequency is too low to confidently rul e out a disease causing role. Computational analyses (biochemical amino acid pro perties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong sup port for or against an impact to the protein. In summary, this variant is more likely to be benign but additional studies are needed to determine this with con fidence. - |
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 | May 23, 2017 | - - |
Primary familial dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Jul 29, 2016 | - - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Hypertrophic cardiomyopathy 14 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | - - |
MYH6-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 28, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 20, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at