ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5561C>T (p.Thr1854Met) (rs372381770)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154324 SCV000203986 uncertain significance not specified 2017-08-29 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr1854Me t variant in MYH7 has been reported in >5 individuals with HCM (Van Driest 2004 reported incorrectly as p.Thr1834Met, Zou 2013, Chiou 2015, Walsh 2016, LMM data ) and in ClinVar (Variation ID 161320). It has been identified in 7/126622 Europ ean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadi nstitute.org/; dbSNP rs372381770). This variant was predicted to be pathogenic u sing a computational tool clinically validated by our laboratory. This tool's pa thogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical sign ificance of the p.Thr1854Met variant is uncertain.
GeneDx RCV000158710 SCV000208645 pathogenic not provided 2013-08-07 criteria provided, single submitter clinical testing p.Thr1854Met (ACG>ATG): c.5561 C>T in exon 38 of the MYH7 gene (NM_000257.2). The Thr1854Met mutation in the MYH7 gene was reported in one individual diagnosed with HCM and not present in 400 normal chromosomes of African American and Caucasian backgrounds. (Of note, due to an error in the Van Driest et al. cited report, the mutation is denoted T1834M) (Van Driest S et al., 2004). In addition, Thr1854Met was identified in three individuals diagnosed with HCM from one family, two of whom were also heterozygous for a variant in the MYBPC3 gene (IVS14-13 G>A) (Page S et al., 2012). Furthermore, Thr1854Met was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Thr1854Met results in a non-conservative amino acid substitution of a hydrophilic, basic Threonine residue with a hydrophobic Methionine. Mutations in nearby residues (Lys1848Thr, Arg1858Met, Arg1863Gln) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. The variant is found in HCM panel(s).
Invitae RCV000457760 SCV000546198 likely pathogenic Hypertrophic cardiomyopathy 2016-07-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1854 of the MYH7 protein (p.Thr1854Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs372381770, ExAC 0.006%). This variant has been reported in several individuals and in one family affected with hypertrophic cardiomyopathy. However, segregation studies have not been reported for this variant (PMID:15358028, 22267749, 25086479, 23283745). This variant has also been reported as p.Thr1834Met in the literature (PMID: 15358028). ClinVar contains an entry for this variant (Variation ID: 161320). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). In summary, this variant is a rare missense change that has been reported in affected individuals and is expected to affect protein function. Therefore, it has been classified as Likely Pathogenic.
Blueprint Genetics RCV000158710 SCV000927530 uncertain significance not provided 2018-02-14 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148695 SCV000190424 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research

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