ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.532A>T (p.Met178Leu)

dbSNP: rs1555418829
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Total submissions: 5
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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 RCV000609399 SCV000731353 uncertain significance not specified 2017-01-06 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Met178Leu variant in ACTC1 has been identified via exome sequencing in 1 Caucasian family with Atrial Septal Defect. The variant was present in 4 affected individuals an d 1 obligate carrier and was not absent in the one unaffected individual tested (Greenway 2014). This variant was absent from large population studies. Computat ional prediction tools and conservation analysis are suggest that the p.Met178Le u variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The ACTC1 gene has previously been associated with ASD (Matson 2008) but the overall data linking this gene to ASD is still li mited. Therefore, while there is some suspicion that the Met178Leu variant caus es ASD its clinical significance is uncertain.
Invitae RCV001302582 SCV001491796 uncertain significance Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2022-05-22 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 178 of the ACTC1 protein (p.Met178Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with isolated secundum atrial septal defect (PMID: 24461919). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 517203). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Ambry Genetics RCV002343165 SCV002640794 uncertain significance Cardiovascular phenotype 2021-12-01 criteria provided, single submitter clinical testing The p.M178L variant (also known as c.532A>T), located in coding exon 3 of the ACTC1 gene, results from an A to T substitution at nucleotide position 532. The methionine at codon 178 is replaced by leucine, an amino acid with highly similar properties. This variant has been detected in several affected members of a family with atrial septal defect (Greenway SC et al. Can J Cardiol, 2014 Feb;30:181-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV001302582 SCV002814434 uncertain significance Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2021-07-29 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004002623 SCV004844832 uncertain significance Hypertrophic cardiomyopathy 2023-11-30 criteria provided, single submitter clinical testing This missense variant replaces methionine with leucine at codon 178 of the ACTC1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in five related individuals affected with atrial septal defect (PMID: 24461919). It has been shown that this variant segregates with disease in this family. This variant has not been identified 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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