Submissions for variant NM_000257.4(MYH7):c.3994G>A (p.Ala1332Thr)

gnomAD frequency: 0.00001  dbSNP: rs397516198

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000685068	SCV000059531	uncertain significance	Hypertrophic cardiomyopathy	2019-04-05	criteria provided, single submitter	clinical testing	Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Seen at the LMM in one individual with HCM and segregated with disease in one relative. It has also been reported in one individual with HCM (Waldmuller 2011). Clinvar: VUS (Invitae, GeneDx, LMM). Gnomad: 0.07% (7 AJ alleles).
GeneDx	RCV000766755	SCV000279571	uncertain significance	not provided	2020-11-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 31534214, 21750094)
Invitae	RCV000685068	SCV000812540	uncertain significance	Hypertrophic cardiomyopathy	2022-03-20	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 1332 of the MYH7 protein (p.Ala1332Thr). This variant is present in population databases (rs397516198, gnomAD 0.07%). This missense change has been observed in individual(s) with MYH7-related conditions (PMID: 21750094, 27532257, 31534214). ClinVar contains an entry for this variant (Variation ID: 42986). 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.
Color Diagnostics, LLC DBA Color Health	RCV001178113	SCV001342469	uncertain significance	Cardiomyopathy	2023-01-24	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1332 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 two individuals affected with hypertrophic cardiomyopathy (PMID: 27532257), in one individual affected with dilated cardiomyopathy (PMID: 21750094), and in one individual affected with sudden cardiac death (PMID: 31534214). This variant has been identified in 8/248764 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.
AiLife Diagnostics, AiLife Diagnostics	RCV000766755	SCV002501346	uncertain significance	not provided	2021-04-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477072	SCV002780822	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-10-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001178113	SCV004817281	uncertain significance	Cardiomyopathy	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1332 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 two individuals affected with hypertrophic cardiomyopathy (PMID: 27532257), in one individual affected with dilated cardiomyopathy (PMID: 21750094), and in one individual affected with sudden cardiac death (PMID: 31534214). This variant has been identified in 8/248764 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	RCV004018778	SCV004945985	uncertain significance	Cardiovascular phenotype	2021-05-07	criteria provided, single submitter	clinical testing	The c.3994G>A (p.A1332T) alteration is located in exon 30 (coding exon 28) of the MYH7 gene. This alteration results from a G to A substitution at nucleotide position 3994, causing the alanine (A) at amino acid position 1332 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000766755	SCV000924868	uncertain significance	not provided	2016-04-05	no assertion criteria provided	provider interpretation