ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.3382G>A (p.Ala1128Thr) (rs199552354)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel RCV000758075 SCV000564444 likely benign Cardiomyopathy 2021-03-22 reviewed by expert panel curation 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
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172567 SCV000051005 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035852 SCV000059503 likely benign not specified 2017-08-06 criteria provided, single submitter clinical testing 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with DCM and 1 adult with HCM - one of the children with DCM i nherited the variant from an unaffected parent (LMM unpublished data).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.
GeneDx RCV000035852 SCV000208540 uncertain significance not specified 2017-02-06 criteria provided, single submitter clinical testing p.Ala1128Thr (GCC>ACC): c.3382 G>A in exon 27 of the MYH7 gene (NM_000257.2). The A1128T variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. A1128T results in a non-conservative amino acid substitution of a non-polar Alanine with a neutral, polar Threonine at a position that is conserved in mammals. While in silico analysis predicts A1128T is benign to the protein structure/function, mutations in nearby codons (E1116K, L1135R) have been reported in association with HCM, suggesting that there is functional importance of this region of the protein. The A1128T variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in HCM,DCM-CRDM panel(s).
Invitae RCV000471337 SCV000546254 uncertain significance Hypertrophic cardiomyopathy 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1128 of the MYH7 protein (p.Ala1128Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs199552354), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 31513939, 27247418). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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.
Center for Human Genetics,University of Leuven RCV000471337 SCV000886835 uncertain significance Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000758075 SCV000902575 uncertain significance Cardiomyopathy 2020-10-27 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 1128 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a dilated cardiomyopathy subject (Rodríguez-García 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000758075 SCV001333905 likely benign Cardiomyopathy 2018-07-27 criteria provided, single submitter clinical testing

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