ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.976G>C (p.Ala326Pro) (rs372731424)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 2019-10-11 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 326 of the MYH7 protein (p.Ala326Pro). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and proline. This variant is present in population databases (rs372731424, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 19666645, 27247418, 27532257), and in an additional individual with hypertrophic cardiomyopathy who inherited the variant from a healthy parent (PMID: 24183960). ClinVar contains an entry for this variant (Variation ID: 43117). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 Familial hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; Myopathy, distal, 1; MYH7-related late-onset scapuloperoneal muscular dystrophy 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778404 SCV000914636 likely pathogenic Familial hypertrophic cardiomyopathy 1 2018-08-16 criteria provided, single submitter clinical testing The MYH7 c.976G>C (p.Ala326Pro) missense variant has been reported in four studies in which it is identified in at least seven individuals with hypertrophic cardiomyopathy (HCM). Michels et al. (2009) found the variant in three individuals who are possibly related, including in one with HCM and in two asymptomatic individuals who were later diagnosed with HCM. D'Argenio et al. (2014) detected the variant in one individual with HCM who inherited the variant from his reportedly healthy father. Homburger et al. (2016) report the variant in four alleles from 2,913 individuals with HCM from the Sarcomeric Human Cardiomyopathy Registry (SHaRe), and Walsh et al. (2017) report the variant in three individuals with HCM. The p.Arg326Pro variant was absent from one control and is reported at a frequency of 0.000150 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the clinical evidence, the p.Arg326Pro variant is classified as likely pathogenic for hypertrophic cardiomyopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Blueprint Genetics RCV000766416 SCV000928253 uncertain significance not provided 2019-02-27 criteria provided, single submitter clinical testing
Mendelics RCV000778404 SCV001139417 uncertain significance Familial hypertrophic cardiomyopathy 1 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001109127 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.
Illumina Clinical Services Laboratory,Illumina RCV001109128 SCV001266436 benign Myopathy, distal, 1 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Color RCV001187131 SCV001353817 uncertain significance Cardiomyopathy 2019-12-30 criteria provided, single submitter clinical testing

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