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

gnomAD frequency: 0.00001  dbSNP: rs143362532

Total submissions: 12

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, Mass General Brigham 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	RCV000172041	SCV000583230	uncertain significance	not provided	2021-06-15	criteria provided, single submitter	clinical testing	Reported in at least one individual in association with HCM (Homburger et al., 2016); however, no further clinical details or segregation data were described; In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance by several clinical laboratories, one of which reported this variant in one Caucasian individual with HCM who harbored a variant in another gene that was sufficient to explain their disease (ClinVar Variant ID# 43073; SCV000059620.5; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 23861362, 23403236, 27247418, 26582918, 27535533)
Invitae	RCV000560402	SCV000623741	uncertain significance	Hypertrophic cardiomyopathy	2022-08-24	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1834 of the MYH7 protein (p.Ala1834Thr). This variant is present in population databases (rs143362532, gnomAD 0.008%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27247418). ClinVar contains an entry for this variant (Variation ID: 43073). 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: "Benign"; 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.
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	2023-03-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV003320087	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 Laboratory Services, Illumina	RCV001109553	SCV001266900	uncertain significance	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 Laboratory Services, Illumina	RCV001115179	SCV001273136	benign	MYH7-related skeletal 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. 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 Diagnostics, LLC DBA Color Health	RCV000770468	SCV001339634	uncertain significance	Cardiomyopathy	2022-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1834 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27247418). This variant has been identified in 14/250566 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.
Ambry Genetics	RCV002345282	SCV002650177	uncertain significance	Cardiovascular phenotype	2022-10-17	criteria provided, single submitter	clinical testing	The p.A1834T variant (also known as c.5500G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide position 5500. The alanine at codon 1834 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort and as a secondary cardiac variant in an exome cohort; however, clinical details were limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6). This amino acid position is not well 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.
Revvity Omics, Revvity	RCV000172041	SCV003817655	uncertain significance	not provided	2022-11-16	criteria provided, single submitter	clinical testing