chr14-23398866-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PP2PP3_StrongBS2
The NM_002471.4(MYH6):c.1753G>A(p.Gly585Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,614,014 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. G585G) has been classified as Likely benign.
Frequency
Consequence
NM_002471.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.1753G>A | p.Gly585Ser | missense_variant | 15/39 | ENST00000405093.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH6 | ENST00000405093.9 | c.1753G>A | p.Gly585Ser | missense_variant | 15/39 | 5 | NM_002471.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000131 AC: 20AN: 152120Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000147 AC: 37AN: 251460Hom.: 0 AF XY: 0.000213 AC XY: 29AN XY: 135922
GnomAD4 exome AF: 0.000124 AC: 182AN: 1461894Hom.: 0 Cov.: 32 AF XY: 0.000143 AC XY: 104AN XY: 727248
GnomAD4 genome AF: 0.000131 AC: 20AN: 152120Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10AN XY: 74310
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 11, 2014 | The Gly585Ser variant in MYH6 has now been identified by our laboratory in one C aucasian adult with RCM, who carried a pathogenic variant in another RCM associa ted gene, and one individual with ischemic cardiomyopathy and congestive heart f ailure. This variant has also been identified in 3/8600 of European American chr omosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS /; dbSNP rs150415679). Computational prediction tools and conservation analyses suggest that the Gly585Ser variant may impact the protein, though this informati on is not predictive enough to determine pathogenicity. In summary, additional i nformation is needed to fully assess its clinical significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 17, 2020 | Variant summary: MYH6 c.1753G>A (p.Gly585Ser) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of 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 0.00015 in 251460 control chromosomes (gnomAD). The observed variant frequency is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.1753G>A has been reported in the literature in at least one individual affected with congenital heart disease (CHD). This report however, does 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. Three other ClinVar submitters (evaluation after 2014) cite 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 | Jan 22, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 585 of the MYH6 protein (p.Gly585Ser). This variant is present in population databases (rs150415679, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of MYH6-related conditions (PMID: 28991257, 31737537, 35456442). ClinVar contains an entry for this variant (Variation ID: 36627). 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 with a positive 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. - |
Atrial septal defect 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 14, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jul 05, 2021 | - - |
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 | Apr 04, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 17, 2018 | A variant of uncertain significance has been identified in the MYH6 gene. The G585S variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G585S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 30, 2021 | The p.G585S variant (also known as c.1753G>A), located in coding exon 13 of the MYH6 gene, results from a G to A substitution at nucleotide position 1753. The glycine at codon 585 is replaced by serine, an amino acid with similar properties. This variant has been detected in an individual referred for dilated cardiomyopathy genetic testing, and in a subject with congenital heart disease who also carried a second missense alteration in MYH6 (Jin SC et al. Nat. Genet., 2017 Nov;49:1593-1601; Marschall C et al. Cardiovasc Diagn Ther. 2019 Oct;9(Suppl 2):S292-S298). 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. - |
Hypertrophic cardiomyopathy 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Oct 21, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at