ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000251618 SCV000320654 uncertain significance Cardiovascular phenotype 2016-07-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
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.
Illumina Clinical Services Laboratory,Illumina RCV000391229 SCV000390713 uncertain significance Atrial septal defect 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000302614 SCV000390714 uncertain significance Left ventricular noncompaction cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000357333 SCV000390715 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000406066 SCV000390716 uncertain significance Familial restrictive cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000299025 SCV000390717 uncertain significance Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000576182 SCV000676951 uncertain significance Familial hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2017-11-22 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) 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000043641 SCV000061993 uncertain significance not specified 2016-12-01 criteria provided, single submitter clinical testing The p.Leu10Met variant in ACTC1 has been reported in a 15 year old individual wi th HCM but no family history (Kindel 2012) and has been identified by our labora tory in 2 individuals with HCM (15 and 4 months). In one of these families the variant was also present in the unaffected mother, raising some concern as to wh ether this variant can be the sole cause of disease. The p.Leu10Met variant has been identified in 2/11548 Latino chromosomes by the Exome Aggregation Consortiu m (ExAC, http://exac.broadinstitute.org; dbSNP rs397517057). Computational predi ction tools and conservation analysis suggest that it may impact the protein, th ough this information is not predictive enough to determine pathogenicity. In su mmary, the clinical significance of the p.Leu10Met variant is uncertain.

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