Submissions for variant NM_000257.4(MYH7):c.5786C>T (p.Thr1929Met)

gnomAD frequency: 0.00010  dbSNP: rs730880918

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000168923	SCV000208810	uncertain significance	not provided	2023-02-07	criteria provided, single submitter	clinical testing	Identified in patients with HCM referred for genetic testing at GeneDx and in published literature (Michels et al., 2009; Kubo et al., 2011; Maron et al., 2012; van Velzen et al., 2016; Pajusalu et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25961035, 21799269, 15358028, 28798025, 28378410, 19666645, 21839045, 27247418, 34426522, 32894683, 27476098, 34542152)
Blueprint Genetics	RCV000208216	SCV000264101	uncertain significance	Primary familial hypertrophic cardiomyopathy	2015-10-15	criteria provided, single submitter	clinical testing
Invitae	RCV000477627	SCV000546252	uncertain significance	Hypertrophic cardiomyopathy	2022-09-06	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 1929 of the MYH7 protein (p.Thr1929Met). This variant is present in population databases (rs730880918, gnomAD 0.009%). This missense change has been observed in individual(s) with left ventricular noncompaction and hypertrophic cardiomyopathy (PMID: 15358028, 19666645, 21799269, 28798025). ClinVar contains an entry for this variant (Variation ID: 181397). 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: "Not Available"; Align-GVGD: "Class C0"). 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.
Ambry Genetics	RCV000620357	SCV000740097	uncertain significance	Cardiovascular phenotype	2022-08-25	criteria provided, single submitter	clinical testing	The p.T1929M variant (also known as c.5786C>T), located in coding exon 37 of the MYH7 gene, results from a C to T substitution at nucleotide position 5786. The threonine at codon 1929 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in association with hypertrophic cardiomyopathy (HCM) (Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Aug;44:602-10; Kubo T et al. Circ. J., 2011 Jul;75:2654-9). This alteration was reported in a proband and three asymptomatic family members (Michels M et al. Eur. Heart J., 2009 Nov;30:2593-8) and has also been reported in conjunction with a second missense alteration in MYH7 (Maron BJ et al. Heart Rhythm, 2012 Jan;9:57-63). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000777941	SCV000914039	uncertain significance	Cardiomyopathy	2023-03-30	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 1929 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individual affected with hypertrophic cardiomyopathy (PMID: 15358028, 19666645, 21799269, 21839045, 28378410, 33495596). One of these individuals also carried a different pathogenic missense variant in the MYH7 (PMID: 28378410). This variant has also been reported in an individual affected with left ventricular noncompaction (PMID: 28798025). This variant has been identified in 15/282610 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000168923	SCV002541603	uncertain significance	not provided	2022-01-19	criteria provided, single submitter	clinical testing