ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.2678A>G (p.Asp893Gly) (rs199920384)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183279 SCV000235706 uncertain significance not provided 2018-03-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ACTN2 gene. The D893G variant has been reported in one individual from a cohort of 166 individuals with schizophrenia or schizoaffective disorder who underwent whole exome or genome sequencing (Need et al., 2012). Of note, the authors found no significant risk for either schizophrenia or schizoaffective disorder associated with any of the rare variants identified in this cohort, including D893G in the ACTN2 gene. Moreover, the absence or presence of cardiac disease was not reported for these individuals. The D893G variant 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. Additionally, D893G is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, this variant has not been identified in a significant number of individuals with cardiomyopathy, and there are no functional studies or segregation data available to clarify the role of this variant in disease. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000472395 SCV000553766 uncertain significance Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2016-12-08 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 893 of the ACTN2 protein (p.Asp893Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs199920384, ExAC 0.006%) but has not been reported in the literature in individuals with an ACTN2-related disease. ClinVar contains an entry for this variant (Variation ID: 201651). 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 disruptive, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function and splicing. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000183279 SCV000924721 uncertain significance not provided 2016-10-28 no assertion criteria provided provider interpretation p.Asp893Gly (c.2678A>G) in exon 21 of the ACTN2 gene (NM_001103.3; hg19 chr1-236925912-A-G) Given limited gene-level evidence to link this gene to HCM, lack of case data, and relatively high frequency in a population dataset, we consider this variant to be of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has not been reported in the literature. We have seen it in one person with HCM. Testing was performed by Invitae. The lab report notes that, 'This sequence change replaces aspartic acid with glycine at codon 893 of the ACTN2 protein (p.Asp893Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine...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 disruptive, but these predictions have not been confirmed by published functional studies.• Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies." The variant was reported online in 6 of 141,114 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 5 of of 63,280 individuals of non-Finnish European descent (0.004% MAF) and 1 of 15,428 South Asian people (0.003% MAF). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Combined variation at this codon is MAF ~0.019%. Two other variants affecting the same codon are listed in gnomAD: Asp893Asn and Asp893Tyr. Asp893Asn was observed in 44 of 141,072 people (0.15% MAF). Specifically, it was seen in 41 of 63,267 non-Finnish European people (MAF 0.03%), 1 of 9,458 East Asian people (0.005% MAF), 1 of 12,921 African people (0.004 MAF), and 1 of 13,002 Finnish people (MAF 0.004%). Asp893Tyr was observed in 1 of 125,955 people. Specifically it was seen in 1 of 15,426 South Asian people (0.003% MAF).

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