ClinVar Miner

Submissions for variant NM_000257.3(MYH7):c.5562G>A (p.Thr1854=) (rs368706722)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617785 SCV000736124 likely benign Cardiovascular phenotype 2017-11-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Synonymous alterations with insufficient evidence to classify as benign
Blueprint Genetics, RCV000157366 SCV000207104 likely benign Primary dilated cardiomyopathy 2014-09-29 no assertion criteria provided clinical testing
Color RCV000777750 SCV000913712 likely benign Cardiomyopathy 2018-08-25 criteria provided, single submitter clinical testing
GeneDx RCV000035970 SCV000519077 benign not specified 2015-10-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000548290 SCV000623746 likely benign Hypertrophic cardiomyopathy 2017-11-06 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035970 SCV000059622 likely benign not specified 2015-02-10 criteria provided, single submitter clinical testing p.Thr1854Thr in exon 38 of MYH7: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 2/8600 European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS).
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786174 SCV000924880 uncertain significance not provided 2017-06-12 no assertion criteria provided provider interpretation p.Thr1854Thr (c.5562G>A (silent); chr14:23883309 ) in the MYH7 gene (NM_000257.3) Given that there are no strong case reports available for this variant and that this variant is present at a high frequency in the general population, we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant is present in ClinVar and is classified as a variant of uncertain significance by one lab, a likely benign variant by two labs and a benign variant by the final lab. This variant may have been reported in the literature, although it is unclear. This is a weak case, as the paper states that two variants were found in 2 individuals with HCM: MYBPC3 IVS14-23G>A in combination with "MYH7 T1854 mol/L." I am unclear if the mol/L is a typo. It is not mentioned again in the paper. It is classified as a disease-causing mutation based on in silico analysis (Page et al 2012). This residue is not enriched in cases vs controls (Homburger et al 2016, amr et al 2016). Per the test report, "Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies." The threonine at codon 1854 is moderately conserved across species, whereas neighboring amino acids are strongly conserved. Another variant at this codon (p.Thr8154Met) is classified as follows in Clinvar (#= number of labs): pathogenic (1) likely pathogenic (1) and as a VUS (2). A nearby variant (p.Glu1856Lys), is reported to be pathogenic for Liang distal myopathy type 1; however, it has not been classified by any clinical labs. The variant was reported online in 34 of 137,831 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 31 of 63,301 individuals of European descent (MAF=0.02%), 3 of 17,206 individuals of Latino descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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