rs199552354
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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.3382G>A (p.Ala1128Thr) variant in MYH7 has been identified in 0.02% (FAF 95% CI; 10/34232) of Latino 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/CA013661/MONDO:0004994/002
Frequency
Genomes: đť‘“ 0.00011 ( 0 hom., cov: 31)
Exomes đť‘“: 0.000065 ( 0 hom. )
Consequence
MYH7
NM_000257.4 missense
NM_000257.4 missense
Scores
2
9
9
Clinical Significance
Conservation
PhyloP100: 2.02
Genes affected
MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS1
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000112 AC: 17AN: 151928Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000112 AC: 27AN: 240554Hom.: 0 AF XY: 0.000115 AC XY: 15AN XY: 130922
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GnomAD4 exome AF: 0.0000653 AC: 95AN: 1454954Hom.: 0 Cov.: 34 AF XY: 0.0000732 AC XY: 53AN XY: 723586
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GnomAD4 genome 0.000112 AC: 17AN: 152046Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6AN XY: 74310
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ClinVar
Significance: Likely benign
Submissions summary: Uncertain:6Benign:6
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Cardiomyopathy Uncertain:2Benign:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 13, 2023 | This missense variant replaces alanine with threonine at codon 1128 of the MYH7 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a dilated cardiomyopathy subject (Rodriguez-Garcia et al., 2011, abstract) as well as in multiple healthy individuals free of cardiovascular disorders (PMID: 23861362, 24510615). This variant has been identified in 26/236012 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 13, 2022 | - - |
| Likely benign, reviewed by expert panel | curation | ClinGen Cardiomyopathy Variant Curation Expert Panel | Mar 22, 2021 | The c.3382G>A (p.Ala1128Thr) variant in MYH7 has been identified in 0.02% (FAF 95% CI; 10/34232) of Latino 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 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces alanine with threonine at codon 1128 of the MYH7 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a dilated cardiomyopathy subject (Rodriguez-Garcia et al., 2011, abstract) as well as in multiple healthy individuals free of cardiovascular disorders (PMID: 23861362, 24510615). This variant has been identified in 26/236012 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 22, 2024 | See Variant Classification Assertion Criteria. - |
| Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 25, 2023 | The MYH7 c.3382G>A; p.Ala1128Thr variant (rs199552354) is reported in the literature in individuals affected with hypertrophic cardiomyopathy (Ho 2018, Luo 2020, Robyns 2020), but is also found in healthy controls (Kapplinger 2014, Ng 2013). This variant is also reported in ClinVar (Variation ID: 42959), and is found in the Latino/Admixed American population with an allele frequency of 0.029% (10/34232 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.404). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Ho CY et al. Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Circulation. 2018 Oct 2;138(14):1387-1398. PMID: 30297972. Kapplinger JD et al. Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise. J Cardiovasc Transl Res. 2014 Apr;7(3):347-61. PMID: 24510615. Luo Q et al. Retrospective analysis of clinical phenotype and prognosis of hypertrophic cardiomyopathy complicated with hypertension. Sci Rep. 2020 Jan 15;10(1):349. PMID: 31941943. Ng D et al. Interpreting secondary cardiac disease variants in an exome cohort. Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. PMID: 23861362. Robyns T et al. Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy. Eur J Med Genet. 2020 Mar;63(3):103754. PMID: 31513939. - |
Hypertrophic cardiomyopathy Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Human Genetics, University of Leuven | Oct 31, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1128 of the MYH7 protein (p.Ala1128Thr). This variant is present in population databases (rs199552354, gnomAD 0.03%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27247418, 31513939). ClinVar contains an entry for this variant (Variation ID: 42959). 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 MYH7 protein function with a positive predictive value of 95%. 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. - |
not specified Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 06, 2017 | The p.Ala1128Thr variant in MYH7 has been reported in 1 individual with DCM (Rod riguez-Garcia 2011 - abstract only). It has also been identified by our laborat ory in 2 children with DCM and 1 adult with HCM - one of the children with DCM i nherited the variant from an unaffected parent (LMM unpublished data). This vari ant has been identified in 26/236012 chromosomes in the gnomAD database (http:// gnomad.broadinstitute.org, dbSNP rs199552354). Computational prediction tools an d conservation analyses do not provide strong support for or against an impact t o the protein. In summary, given the inconsistent phenotypic observations (both DCM and HCM), 26 occurrences in the general population, and lack of disease in a carrier parent of an affected child, the clinical significance of the p.Ala1128 Thr variant is likely benign. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 15, 2023 | Variant summary: MYH7 c.3382G>A (p.Ala1128Thr) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 240554 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYH7 causing Cardiomyopathy (0.00011 vs 0.0013), allowing no conclusion about variant significance. c.3382G>A has been reported in the literature in individuals affected with Cardiomyopathy (Homburger_2016, Ho_2018, Kelly_2018, Luo_2020, Robyns_2020), but it has also been reported in unaffected individuals (Ng_2013, Kapplinger_2014). Furthermore, one ClinVar submitter reports internal data of the variant identified in 2 children with DCM and 1 adult with HCM, with one of the children with DCM having inherited the variant from an unaffected parent (SCV000059503.5). A co-occurrence with a pathogenic variant has been reported (TTN c.3382G>A, p.Gln12086X; Internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23861362, 24510615, 27247418, 27930701, 29300372, 30297972, 31513939, 31941943). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Four ClinVar submitters including an expert panel (ClinGen Cardiomyopathy Variant Curation Expert Panel) (evaluation after 2014) cite the variant as likely benign and four ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 24, 2023 | 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
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at