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

gnomAD frequency: 0.00002  dbSNP: rs372381770

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154324	SCV000203986	uncertain significance	not specified	2020-04-20	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr1854Met variant in MYH7 has been reported in >6 individuals with HCM (Van Dreist 2004 PMID: 15358028; reported incorrectly as p.Thr1834Met, Page 2012 PMID:22267749, Zou 2013 PMID:23283745, Chiou 2015 PMID:25086479, Walsh 2017 PMID:27532257, Wang 2019 PMID:31638223, LMM data) and by other clinical laboratories in ClinVar (Variation ID 161320). It has also been identified in 7/126622 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Thr1854Met variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PP3.
GeneDx	RCV000158710	SCV000208645	uncertain significance	not provided	2022-02-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 23299917, 27532257, 15358028, 25086479, 23283745, 31638223, 31737537, 22267749)
Invitae	RCV000457760	SCV000546198	likely pathogenic	Hypertrophic cardiomyopathy	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1854 of the MYH7 protein (p.Thr1854Met). This variant is present in population databases (rs372381770, gnomAD 0.006%). This missense change has been observed in individuals with autosomal dominant hypertrophic cardiomyopathy (PMID: 15358028, 23283745, 25086479, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 161320). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Blueprint Genetics	RCV000158710	SCV000927530	uncertain significance	not provided	2018-02-14	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170482	SCV001333063	uncertain significance	Cardiomyopathy	2022-07-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345456	SCV002653137	uncertain significance	Cardiovascular phenotype	2022-12-16	criteria provided, single submitter	clinical testing	The p.T1854M variant (also known as c.5561C>T), located in coding exon 36 of the MYH7 gene, results from a C to T substitution at nucleotide position 5561. The threonine at codon 1854 is replaced by methionine, an amino acid with similar properties. This variant has been detected in hypertrophic cardiomyopathy (HCM) cohorts for which clinical detail was limited (Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Aug;44:602-10 (reported as T1834M); Zou Y et al. Mol. Biol. Rep., 2013 Jun;40:3969-76; Chiou KR et al. J Cardiol, 2015 Mar;65:250-6; Walsh R et al. Genet. Med., 2017 02;19:192-203), and has been reported to co-occur with variants in other cardiomyopathy-related genes in individuals with HCM (Page SP et al. Circ Cardiovasc Genet, 2012 Apr;5:156-66; Bonaventura J et al. Arch Med Sci, 2019 May;15:641-649). This variant has also been detected in exome cohorts, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000158710	SCV003815411	uncertain significance	not provided	2023-06-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170482	SCV004359500	likely pathogenic	Cardiomyopathy	2023-11-27	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 1854 in the LMM domain of the MYH7 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 15358028 ,25086479, 27532257, 23283745, 31110529, 31638223, 33495597, 34912951, 37121957; communication with an external laboratory; ClinVar SCV000546198.5). It has also been reported in one individual affected with dilated cardiomyopathy (PMID: 37461109) and in one individual affected with ischemic stroke (PMID: 36973604). This variant has been identified in 8/281196 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
CSER _CC_NCGL, University of Washington	RCV000148695	SCV000190424	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-06-01	no assertion criteria provided	research