Submissions for variant NM_001103.4(ACTN2):c.2578C>T (p.Gln860Ter)

dbSNP: rs763078071

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183277	SCV000235704	pathogenic	not provided	2013-01-28	criteria provided, single submitter	clinical testing	The Gln860Stop mutation in the ACTN2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Gln860Stop is located within the last exon of the ACTN2 gene, and is predicted to cause loss of normal protein function by protein truncation. While most of the disease-causing mutations in the ACTN2 gene are missense changes, a frameshift deletion located at the penultimate exon has been reported in association with DCM. In summary, Gln860Stop in the ACTN2 gene is interpreted as a disease-causing mutation. The variant is found in DCM panel(s).
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223773	SCV000280041	uncertain significance	not specified	2013-02-27	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. Given the data reviewed below we consider this to be a variant of uncertain significance, likely disease causing. The variant is novel. This is a nonsense variant; a single nucleotide substitution creates a premature stop codon at codon 860. It occurs in the last exon of ACTN2. Given this position it is predicted that this leads to a truncated protein product (opposed to no protein product by way of nonsense mediated mRNA decay). The protein is 894 amino acids long, so the truncated protein would be missing the last 34 amino acids. Multiple groups have found that the c-terminal 72 amino acids of alpha-actinin are responsible for titin binding (Ohtsukia et al 1997, Sorimachi et al 1997, Joseph et al 2001). Ohtsuka et al (1997) also noted that alpha-actinin lacking the c-terminal 21 amino acids did not bind to titin. In total the variant has not been seen in ~6500 published controls and individuals from publicly available population datasets. There are no nonsense, frameshift, or splice variants listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of February 26th, 2013). 61 out of ~6500 individuals (0.9%) in the NHLBI exome sequencing project have a non-synonymous variant that was present in 1-3 individuals in that sample. dbSNP has entries for two other loss of function/truncating variants: p.Glu505Ter (rs34193420) with no allele frequency data, and p.Val127AspfsX20 (rs201411937), submitted based on observation in a sample of 10 Korean individuals.