rs187073962
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1
This summary comes from the ClinGen Evidence Repository: The c.5704G>C (p.Glu1902Gln) variant in MYH7 has been identified in 0.096% (FAF 95% CI; 27/19954) of East Asian chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Allowing a variant to reach a likely benign classification based on BS1 alone represents a revision of the original ACMG/AMP framework by ClinGen’s Sequence Variant Interpretation Working Group (Tavtigian 2018 PMID:29300386). In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BS1 LINK:https://erepo.genome.network/evrepo/ui/classification/CA016398/MONDO:0004994/002
Frequency
Consequence
NM_000257.4 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 |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.5704G>C | p.Glu1902Gln | missense_variant | 39/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.5704G>C | p.Glu1902Gln | missense_variant | 38/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.5704G>C | p.Glu1902Gln | missense_variant | 39/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152254Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000103 AC: 26AN: 251484Hom.: 0 AF XY: 0.0000956 AC XY: 13AN XY: 135918
GnomAD4 exome AF: 0.0000356 AC: 52AN: 1461894Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23AN XY: 727248
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152372Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74512
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | - | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Glu1902Gln (p.E1902Q; c.5704G>C) in MYH7. This variant is novel. This variant results in glutamate at codon 1902 replaced by glutamine, an amino acid with similar properties. In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging, but tolerated by SIFT. Mutation Taster predicts this variant to be disease causing. The glutamate at codon 1902 is conserved across species, as are neighboring amino acids. No other variants have been reported in association with disease at this codon and nearby codons. In total the variant has not been seen in ~6,000 published controls and individuals from publicly available population datasets. There is no variation at codon 1902 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,000 Caucasian and African American individuals (as of 5/15/13). Note that this dataset does not match the patient's ancestry (FIlipino). Based on data from the 1000 genomes project, the C-allele has an overal frequency of approximately 0.09% (2/2189). This amino acid position is well conserved on sequence alignment. The observed C-allele occurred in the Japanese population at a frequency of 1.12% (2/179). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 05, 2016 | proposed classification - variant undergoing re-assessment, contact laboratory - |
not provided Uncertain:2
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 | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Cardiomyopathy Benign:2
Likely benign, reviewed by expert panel | curation | ClinGen Cardiomyopathy Variant Curation Expert Panel | Mar 22, 2021 | The c.5704G>C (p.Glu1902Gln) variant in MYH7 has been identified in 0.096% (FAF 95% CI; 27/19954) of East Asian chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Allowing a variant to reach a likely benign classification based on BS1 alone represents a revision of the original ACMG/AMP framework by ClinGen’s Sequence Variant Interpretation Working Group (Tavtigian 2018 PMID: 29300386). In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BS1 - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 03, 2021 | - - |
Hypertrophic cardiomyopathy Benign:2
Likely benign, criteria provided, single submitter | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | Feb 07, 2018 | MYH7 Glu1902Gln has been previously identified in HCM patients (Walsh R, et al., 2017; Chiou KR, et al., 2015), as well as a patient with heart failure and atrioventricular block (Liu N, et al., 2017). We identified this variant in a HCM proband of Korean descent. The proband has no family history of disease or sudden death. The variant is present in the Exome Aggregation Consortium dataset (MAF= 0.00007 http://exac.broadinstitute.org/) as well as the Genome Aggregation Database (MAF=0.000087), and is particularly common in East Asian populations (AF= 0.0001, http://gnomad.broadinstitute.org/). In silico tools MutationTaster and PolyPhen-2 predict this variant to be deleterious, however SIFT predicts this variant to be "Tolerated". In summary, although the variant has been identified in HCM cases these are likely to be incidental findings as the variant is present at a higher than expected frequency in the general population, furthermore in silico predictions are conflicting, therefore we classify MYH7 Glu1902Gln as 'likely benign' - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2023 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 04, 2020 | The p.E1902Q variant (also known as c.5704G>C), located in coding exon 37 of the MYH7 gene, results from a G to C substitution at nucleotide position 5704. The glutamic acid at codon 1902 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in an individual with hypertrophic cardiomyopathy (HCM), an atrioventricular block case with left ventricular hypertrophy, and in HCM genetic testing cohorts; however, in some cases clinical details were limited and/or additional cardiac variants were detected (Chiou KR et al. J Cardiol, 2015 Mar;65:250-6; Walsh R et al. Genet. Med., 2017 02;19:192-203; Liu N et al. Sci Rep, 2017 09;7:10676). 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. - |
Dilated cardiomyopathy 1S Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Myosin storage myopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
MYH7-related skeletal myopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Left ventricular noncompaction cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
MYH7-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 25, 2022 | 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). - |
Hypertrophic cardiomyopathy 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at