ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5500G>A (p.Ala1834Thr) (rs143362532)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172041 SCV000054823 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035968 SCV000059620 uncertain significance not specified 2015-02-25 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Ala1834Thr va riant in MYH7 has been identified by our laboratory in 1 Caucasian individual wi th HCM who carried a variant in another gene that was sufficient to explain thei r disease. This variant has also been identified in 4/66670 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSN P rs143362532). Alanine (Ala) at position 1834 is not conserved in mammals or ev olutionarily distant species and the change to threonine (Thr) was predicted to be benign using a computational tool clinically validated by our laboratory. Thi s tool's benign prediction is estimated to be correct 89% of the time (Jordan 20 11). In summary, while the clinical significance of the p.Ala1834Thr variant is uncertain, these data suggest that it is more likely to be benign.
GeneDx RCV000035968 SCV000583230 uncertain significance not specified 2017-04-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH7 gene. The A1834T variant has been previously reported in at least one individual in association with HCM (Homburger et al., 2016); however, no further clinical details or segregation studies were described. The A1834T variant has also been observed in 4/66670 (0.006%) alleles from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, this variant has been observed in one individual from a cohort of individuals who underwent exome sequencing but were not selected for a clinical history of cardiomyopathy or arrhythmia, or a family history of sudden cardiac death (Ng et al., 2013); although a follow-up cardiac evaluation was not reported. While A1834T 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, this substitution occurs at a position that is not conserved across species and threonine (T) is the wild-type residue at this position in one non-mammalian species. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function. Lastly, the A1834T variant is also classified in ClinVar as a variant of uncertain clinical significance by one other clinical laboratory (ClinVar SCV000059620.4; Landrum et al., 2016).
Invitae RCV000560402 SCV000623741 uncertain significance Hypertrophic cardiomyopathy 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1834 of the MYH7 protein (p.Ala1834Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs143362532, ExAC 0.006%). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27247418). ClinVar contains an entry for this variant (Variation ID: 43073). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be tolerated. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000627131 SCV000747945 uncertain significance Primary familial hypertrophic cardiomyopathy 2017-04-21 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770468 SCV000901911 uncertain significance Cardiomyopathy 2017-04-18 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001109552 SCV001266899 uncertain significance Myosin storage myopathy 2017-11-20 criteria provided, single submitter clinical testing 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001109553 SCV001266900 uncertain significance Familial hypertrophic cardiomyopathy 1 2017-11-20 criteria provided, single submitter clinical testing 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001115179 SCV001273136 benign Myopathy, distal, 1 2017-11-20 criteria provided, single submitter clinical testing 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 rule this variant out of causing disease. Therefore, this variant is classified as benign.
Color RCV000770468 SCV001339634 uncertain significance Cardiomyopathy 2019-11-08 criteria provided, single submitter clinical testing

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