ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.275_277del (p.Phe92del) (rs730880388)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157773 SCV000207703 pathogenic not provided 2013-07-26 criteria provided, single submitter clinical testing The c.275_277delTCT mutation in the ACTC1 gene has been reported in one pre-adolescent individual with HCM and it was absent from 200 control individuals (reported as F92del) (Kaski J et al., 2009). c.275_277delTCT results in an in-frame deletion of a Phenylalanine at codon 92 in the ACTC1 gene. Also, the c.275_277delTCT mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.275_277delTCT in the ACTC1 gene is interpreted as a disease-causing mutation.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000157773 SCV000280035 likely pathogenic not provided 2014-12-03 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. We classify this variant as likely disease-causing. This variant has been previously reported in 1 pre-adolescent individual with HCM (Kaski et al. 2009). There is no published segregation data. This is a deletion of an entire amino acid. The Phenylalanine at this location is absolutely conserved across 100 vertebrate species. The surrounding residues are also very highly conserved. This is the only single amino acid deletion in ACTC1 listed in HGMD as of January 2014. Variation at the following nearby residues have been reported in the HGMD to be associated with HCM: His90Tyr, Arg97Cys, Glu101Lys. This supports the functional importance of this region of the protein. It has not been seen in 6700 individuals from control groups or publicly available population datasets. Kaski et al. (2009) report that it was absent from 200 control individuals. It is also absent from ~6500 individuals of European and African-American ancestry in the NHLBI Exome Sequencing Project. In fact, there is no protein variation in ACTC1 listed in ESP within 100 amino acids of this location, which points to how little variation is typically found in this protein (http://evs.gs.washington.edu/EVS/). There is no variation at this codon listed in 1000 genomes. There is also no variant listed in 1000 genomes that alters an amino acid in ACTC1 as of December 3, 2014.

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