Submissions for variant NM_000257.4(MYH7):c.3982G>A (p.Ala1328Thr)

gnomAD frequency: 0.00011  dbSNP: rs372727092

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656922	SCV000208561	uncertain significance	not provided	2022-08-31	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: 27532257, 24503780, 30511546, 34542152)
Ambry Genetics	RCV000242742	SCV000320380	uncertain significance	Cardiovascular phenotype	2022-04-04	criteria provided, single submitter	clinical testing	The c.3982G>A (p.A1328T) 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 3982, causing the alanine (A) at amino acid position 1328 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Invitae	RCV000532006	SCV000623710	uncertain significance	Hypertrophic cardiomyopathy	2024-01-22	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 1328 of the MYH7 protein (p.Ala1328Thr). This variant is present in population databases (rs372727092, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy or hypertrophic cardiomyopathy (PMID: 24503780, 27532257, 30511546). ClinVar contains an entry for this variant (Variation ID: 42985). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. 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.
Fulgent Genetics, Fulgent Genetics	RCV000765158	SCV000896387	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	2021-09-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001189927	SCV001357321	uncertain significance	Cardiomyopathy	2022-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1328 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 individuals affected with dilated cardiomyopathy (PMID: 27532257, 35470680). This variant has also been reported in an individual affected with hypertrophic cardiomyopathy and in two asymptomatic family members of the family (PMID: 30511546). This variant has been identified in 6/278552 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.
Revvity Omics, Revvity	RCV000656922	SCV003815397	uncertain significance	not provided	2020-10-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001189927	SCV004814388	uncertain significance	Cardiomyopathy	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1328 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 individuals affected with dilated cardiomyopathy (PMID: 27532257, 35470680). This variant has also been reported in an individual affected with hypertrophic cardiomyopathy and in two asymptomatic family members of the family (PMID: 30511546). This variant has been identified in 6/278552 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035879	SCV000059530	uncertain significance	not specified	2014-01-17	no assertion criteria provided	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000035879	SCV000280343	uncertain significance	not specified	2013-06-20	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg238His (R238H; c.713 G>A) in the MYBPC3 gene Based on the data reviewed below, we consider this a variant of unknown significance (VUS). Variants with this classification are not suitable for predictive testing of family members, and they require more investigation. This variant has been reported previously in 2 unrelated cases of DCM, with difficult-to-interpret segregation data available from one family (Waldmiller et al. 2011, Supplementary Data; Pugh et al. 2014-Supplementary Data from Laboratory for Molecular Medicine). Waldmiller et al. found it in a Caucasian patient with DCM recruited in Germany. This is a conservative amino acid change from a positively-charged arginine to a positively-charged histidine, although the side-chains are very different in shape. The arginine at codon 238 is highly conserved (100% across 9 vertebrate species) as are the amino acids on either side. In silico analysis with PolyPhen-2 predicts the variant to be “probably damaging” with a score of 1.0. Missense variants at nearby residues have been listed in HGMD in association with cardiomyopathy, supporting the functional importance of this region of the protein. In particular, 3 different amino acid variants at the adjacent codon 237 have been seen in association with cardiomyopathy: Asp228Asn, Ser236Gly, Tyr237Cys, Tyr237His, Tyr237Ser, Glu240Asp, Ser242Pro (HGMD professional version as of January 17, 2014). In total the variant has not been seen in ~6200 individuals from population datasets. It is not listed in the NHLBI Exome Sequencing Project (ESP) dataset, which currently includes variant calls on ~4200 Caucasian and ~2000 African American individuals. None of these individuals are ancestry-matched to our patient, whose ancestry is Mexican. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is no variant at codon 238 listed in dbSNP or 1000 genomes (as of March 18, 2014).