ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.28C>A (p.Leu10Met) (rs397517057)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000043641 SCV000061993 uncertain significance not specified 2019-06-28 criteria provided, single submitter clinical testing The p.Leu10Met variant in ACTC1 has been identified in 3 individuals with HCM (Kindel 2012, Miller 2013, Alejandra 2017, LMM data) and has been identified in 9/282084 chromosomes by gnomAD (http://exac.broadinstitute.org). It has also been reported in ClinVar (Variation ID #50936). Computational prediction tools and conservation analysis do not provide strong evidence for or against an impact to the protien. In summary, the clinical significance of the p.Leu10Met variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting.
GeneDx RCV000766333 SCV000207706 uncertain significance not provided 2018-07-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ACTC1 gene. The L10M variant has previously been reported in association with HCM (Kindel et al., 2012; Miller et al., 2013; Alejandra et al., 2017; Walsh et al., 2017). This variant has also been identified in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. However, segregation data are currently limited and one individual tested at GeneDx harbors a pathogenic variant in another gene which likely explains their disease. The L10M variant is observed in 3/33,558 alleles from individuals of Latino ancestry and 4/111,186 alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). L10M is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, 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.
Ambry Genetics RCV000251618 SCV000320654 uncertain significance Cardiovascular phenotype 2018-11-15 criteria provided, single submitter clinical testing Insufficient evidence
Illumina Clinical Services Laboratory,Illumina RCV000357333 SCV000390715 uncertain significance Dilated cardiomyopathy 1R 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000853308 SCV000390717 uncertain significance Familial hypertrophic cardiomyopathy 11 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000576182 SCV000676951 uncertain significance Familial hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2019-05-03 criteria provided, single submitter clinical testing This sequence change replaces leucine with methionine at codon 10 of the ACTC1 protein (p.Leu10Met). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and methionine. This variant is present in population databases (rs397517057, ExAC 0.02%). This variant has been reported in individuals with hypertrophic cardiomyopathy (PMID: 22555271, 27532257, 23054336) ClinVar contains an entry for this variant (Variation ID: 50936). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; 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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853308 SCV000996154 likely pathogenic Familial hypertrophic cardiomyopathy 11 2018-06-08 criteria provided, single submitter clinical testing This variant has been detected and reported in at least four individuals with hypertrophic cardiomyopathy in the literature (PMID: 22555271, 27532257, 28138913) including an individual with pediatric onset disease (PMID: 22555271). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (8/245,538) and thus is presumed to be rare. The c.28C>A (p.Leu10Met) variant affects a highly conserved amino acid (up to Baker's yeast, considering 12 species) and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.28C>A (p.Leu10Met) variant is classified as likely pathogenic.
Color RCV001185059 SCV001351198 uncertain significance Cardiomyopathy 2019-10-02 criteria provided, single submitter clinical testing

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