ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.893G>A (p.Arg298His) (rs142482143)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036924 SCV000060579 uncertain significance not specified 2017-01-30 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Arg298His var iant in ACTN2 has been identified by our laboratory in 1 individual with LVNC, 1 with DCM, and 1 with HCM. However, at least one of these individuals carried an additional variant sufficient to explain disease. This variant has also been re ported in ClinVar (Variation ID: 43951). This variant has been identified in 0.1 % (61/66736) of European chromosomes, including 1 homozygote, by the Exome Aggre gation Consortium (ExAC,; dbSNP rs142482143). Com putational prediction tools and conservation analysis suggest that the p.Arg298H is variant may impact the protein, though this information is not predictive eno ugh to determine pathogenicity. In summary, while the clinical significance of t he p.Arg298His variant is uncertain, its frequency suggests that it is more like ly to be benign.
GeneDx RCV000036924 SCV000235681 likely benign not specified 2017-09-20 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV001083559 SCV000553758 likely benign Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2020-10-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000619912 SCV000736008 likely benign Cardiovascular phenotype 2020-02-25 criteria provided, single submitter clinical testing Other strong data supporting benign classification
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768727 SCV000900097 uncertain significance Cardiomyopathy 2015-09-15 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000786082 SCV001147733 uncertain significance not provided 2018-06-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001100765 SCV001257301 uncertain significance Dilated cardiomyopathy 1AA 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786082 SCV000924716 uncertain significance not provided 2017-04-13 no assertion criteria provided provider interpretation Given the weak case data and frequency in the general population databases, we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has was identified in one patient with HCM at our center. Testing was performed at Invitae. It has been seen elsewhere in one case of DCM and one case of LVNC. There is weak case data. Pugh et al. (2014) reports the variant was present in one case of DCM. Testing was done by LMM and, at that time. No other clinical data was available. In silico data are conflicting on predicted effect of this variant on protein function. The variant is present in 126 of 138,513 individuals listed in the Genome Aggregation Consortium Dataset (gnomAD;, which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically the variant has been seen in 109 of 63,292 individuals of European descent (MAF = 0.086%). Of note, one of these individuals is homozygous for the variant. It has also been seen in 11 of 17,210 individuals of Latino descent (MAF = 0.03196%), 1 of 5076 Ashkenazi Jewish individual (MAF = 0.00985%), 2 of 15,391 individuals of South Asian descent, one of which is homozygous (MAF = 0.009746). It is also present at smaller frequencies in the Finnish and East Asian populations. The average coverage at that site in gnomAD is 90x.

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