ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs397517057
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham 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 2023-09-13 criteria provided, single submitter clinical testing Reported in individuals in association with HCM and cardiomyopathy with ventricular arrhythmia (Kindel et al., 2012; Miller et al., 2013; Walsh et al., 2017; Alejandra Restrepo-Cordoba et al., 2017; Clark et al., 2019); however, no segregation studies were described and one individual with HCM also harbored a splice variant in the MYBPC3 gene; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 23054336, 22555271, 28138913, 31019026)
Ambry Genetics RCV000251618 SCV000320654 uncertain significance Cardiovascular phenotype 2022-11-29 criteria provided, single submitter clinical testing The c.28C>A (p.L10M) alteration is located in exon 2 (coding exon 1) of the ACTC1 gene. This alteration results from a C to A substitution at nucleotide position 28, causing the leucine (L) at amino acid position 10 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, 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 Laboratory Services, Illumina RCV000853308 SCV000390717 uncertain significance 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 likely pathogenic Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2023-12-23 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 10 of the ACTC1 protein (p.Leu10Met). This variant is present in population databases (rs397517057, gnomAD 0.009%). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 2255271; Invitae). ClinVar contains an entry for this variant (Variation ID: 50936). 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 not expected to disrupt ACTC1 protein function with a negative predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853308 SCV000996154 likely pathogenic 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 Diagnostics, LLC DBA Color Health RCV001185059 SCV001351198 uncertain significance Cardiomyopathy 2023-05-22 criteria provided, single submitter clinical testing This missense variant replaces leucine with methionine at codon 10 of the ACTC1 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 hypertrophic cardiomyopathy (PMID: 22555271, 23054336, 27532257, 28138913, 35026164; communication with an external laboratory; ClinVar SCV000676951.5). In one case, this variant was reported in an individual affected with hypertrophic cardiomyopathy and poor clinical course who also carried a pathogenic splice variant in the MYBPC3 gene (PMID: 28138913). This variant has also been reported in a young individual affected with ventricular fibrillation and cardiac arrest (PMID: 31246743). This variant has been identified in 9/282084 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 RCV001185059 SCV002043342 uncertain significance Cardiomyopathy 2019-11-20 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003996470 SCV004844875 uncertain significance Hypertrophic cardiomyopathy 2023-12-01 criteria provided, single submitter clinical testing This missense variant replaces leucine with methionine at codon 10 of the ACTC1 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 hypertrophic cardiomyopathy (PMID: 22555271, 23054336, 27532257, 28138913, 35026164; communication with an external laboratory; ClinVar SCV000676951.5). In one case, this variant was reported in an individual affected with hypertrophic cardiomyopathy and poor clinical course who also carried a pathogenic splice variant in the MYBPC3 gene (PMID: 28138913). This variant has also been reported in a young individual affected with ventricular fibrillation and cardiac arrest (PMID: 31246743). This variant has been identified in 9/282084 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.

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