ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.3982G>A (p.Ala1328Thr) (rs372727092)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656922 SCV000208561 uncertain significance not provided 2018-03-27 criteria provided, single submitter clinical testing The A1328T variant of uncertain significance in the MYH7 gene has been previously reported independently of additional cardiogenetic variants in a 1-month old female with DCM (Pugh et al., 2014). This variant has also been identified both independently and in conjunction with additional cardiogenetic variants in individuals referred for cardiomyopathy genetic testing at GeneDx; however, segregation data has been uninformative thus far. In addition, A1328T has also been observed in 0.015% (5/34,248) of alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). The A1328T 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. Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics RCV000242742 SCV000320380 uncertain significance Cardiovascular phenotype 2016-09-07 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000532006 SCV000623710 uncertain significance Hypertrophic cardiomyopathy 2019-07-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1328 of the MYH7 protein (p.Ala1328Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs372727092, ExAC 0.03%). This variant has been reported in individuals affected with dilated cardiomyopathy and hypertrophic cardiomyopathy (PMID: 24503780, 27532257, 30511546). ClinVar contains an entry for this variant (Variation ID: 42985). 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, this variant has uncertain impact on MYH7 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics RCV000765158 SCV000896387 uncertain significance Familial hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; Myopathy, distal, 1; MYH7-related late-onset scapuloperoneal muscular dystrophy 2018-10-31 criteria provided, single submitter clinical testing
Color RCV001189927 SCV001357321 uncertain significance Cardiomyopathy 2020-02-19 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035879 SCV000059530 uncertain significance not specified 2014-01-17 no assertion criteria provided clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000035879 SCV000280343 uncertain significance not specified 2013-06-20 no assertion criteria provided clinical testing 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.Arg238His (R238H; c.713 G>A) in the MYBPC3 gene Based on the data reviewed below, we consider this a variant of unknown significance (VUS). Variants with this classification are not suitable for predictive testing of family members, and they require more investigation. This variant has been reported previously in 2 unrelated cases of DCM, with difficult-to-interpret segregation data available from one family (Waldmiller et al. 2011, Supplementary Data; Pugh et al. 2014-Supplementary Data from Laboratory for Molecular Medicine). Waldmiller et al. found it in a Caucasian patient with DCM recruited in Germany. This is a conservative amino acid change from a positively-charged arginine to a positively-charged histidine, although the side-chains are very different in shape. The arginine at codon 238 is highly conserved (100% across 9 vertebrate species) as are the amino acids on either side. In silico analysis with PolyPhen-2 predicts the variant to be “probably damaging” with a score of 1.0. Missense variants at nearby residues have been listed in HGMD in association with cardiomyopathy, supporting the functional importance of this region of the protein. In particular, 3 different amino acid variants at the adjacent codon 237 have been seen in association with cardiomyopathy: Asp228Asn, Ser236Gly, Tyr237Cys, Tyr237His, Tyr237Ser, Glu240Asp, Ser242Pro (HGMD professional version as of January 17, 2014). In total the variant has not been seen in ~6200 individuals from population datasets. It is not listed in the NHLBI Exome Sequencing Project (ESP) dataset, which currently includes variant calls on ~4200 Caucasian and ~2000 African American individuals. None of these individuals are ancestry-matched to our patient, whose ancestry is Mexican. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is no variant at codon 238 listed in dbSNP or 1000 genomes (as of March 18, 2014).

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