Submissions for variant NM_000257.4(MYH7):c.976G>C (p.Ala326Pro)

gnomAD frequency: 0.00010  dbSNP: rs372731424

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036015	SCV000059667	uncertain significance	not specified	2017-08-30	criteria provided, single submitter	clinical testing	The p.Ala326Pro variant has been reported in 3 individuals with HCM (Michels 200 9, D'Argenio 2014, LMM data). It has been identified in 19/126594 European chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org/; dbSNP rs372731424). Furthermore, alanine (Ala) at position 326 is not cons erved in mammals or evolutionarily distant species, and the change to proline (P ro) was predicted to be benign using a computational tool clinically validated b y our laboratory. This tool's benign prediction is estimated to be correct 89% o f the time (Jordan 2011). In summary, due to conflicting data, the clinical sign ificance of the p.Ala326Pro variant is uncertain.
CSER _CC_NCGL, University of Washington	RCV000148710	SCV000190440	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx	RCV000766416	SCV000208712	uncertain significance	not provided	2018-12-03	criteria provided, single submitter	clinical testing	The A326P variant of uncertain significance in the MYH7 gene has been reported in association with HCM (Michels et al., 2009; D'Argenio et al, 2014; Homburger et al., 2016; Walsh et al., 2017). Michels et al. (2009) identified A326P in two unrelated probands with HCM as well as in two asymptomatic relatives, who had mild evidence of HCM upon clinical evaluation. A326P was also identified in an individual diagnosed with HCM shortly after birth, who harbored additional variants in the MYH7 and INS-IGF2 genes (D'Argenio et al, 2014). The A326P variant was inherited from the proband's clinically unaffected father (D'Argenio et al, 2014). This variant has also been identified, both independently and in conjunction with additional cardiogenetic variants, in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx; segregation data are limited or absent due to the lack of clinical information provided and/or insufficient participation by informative family members.The A326P variant is observed in 19/126,594 (0.015%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). A326P is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In addition, this variant is located in the myosin motor domain, a region enriched with missense variants reported in association with HCM (Walsh et al., 2017; Kelly et al., 2018). However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae	RCV000227951	SCV000284300	uncertain significance	Hypertrophic cardiomyopathy	2022-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 326 of the MYH7 protein (p.Ala326Pro). This variant is present in population databases (rs372731424, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 19666645, 24183960, 27247418, 27532257, 31513939). ClinVar contains an entry for this variant (Variation ID: 43117). 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. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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.
Center for Human Genetics, University of Leuven	RCV000227951	SCV000886831	uncertain significance	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763914	SCV000894855	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	2018-10-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000766416	SCV000928253	uncertain significance	not provided	2019-02-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000778404	SCV001139417	uncertain significance	Hypertrophic cardiomyopathy 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV003320095	SCV001266435	uncertain significance	Myosin storage myopathy	2017-09-06	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV001187131	SCV001353817	uncertain significance	Cardiomyopathy	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with proline at codon 326 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 19666645, 24183960, 27247418, 27476098, 27532257, 30696458, 31323898, 32369506, 33495597, 37466024) and in an individual affected with noncompaction cardiomyopathy (PMID: 29447731). A family member of one proband was a healthy carrier (PMID: 24183960). This variant has also been identified in 25/282608 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001187131	SCV002042707	uncertain significance	Cardiomyopathy	2021-12-08	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000778404	SCV002761854	uncertain significance	Hypertrophic cardiomyopathy 1	2021-12-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162310	SCV003913558	uncertain significance	Cardiovascular phenotype	2023-02-24	criteria provided, single submitter	clinical testing	The p.A326P variant (also known as c.976G>C), located in coding exon 9 of the MYH7 gene, results from a G to C substitution at nucleotide position 976. The alanine at codon 326 is replaced by proline, an amino acid with highly similar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM), however, it was also noted in unaffected/asymptomatic family members (Michels M et al. Eur Heart J, 2009 Nov;30:2593-8; D'Argenio V et al. J Mol Diagn, 2014 Jan;16:32-44; Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; van Waning JI et al. J Am Coll Cardiol, 2018 02;71:711-722; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). This variant has also been reported in exome cohorts (Andreasen C et al. Eur J Hum Genet, 2013 Sep;21:918-28; Maxwell KN et al. Am J Hum Genet, 2016 May;98:801-817). This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). 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.