Submissions for variant NM_001103.4(ACTN2):c.893G>A (p.Arg298His)

gnomAD frequency: 0.00042  dbSNP: rs142482143

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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, http://exac.broadinstitute.org; 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	RCV000786082	SCV000235681	likely benign	not provided	2019-08-02	criteria provided, single submitter	clinical testing	R298H variant in the ACTN2 gene has not been reported as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Although R298H results in a conservative amino acid substitution of one positively charged residue for another, the Arg298 position is conserved across species. In silico analysis predicts R298H is damaging to the protein structure/function. However, no mutations have been reported in association with cardiomyopathy in nearby residues. Furthermore, the NHLBI ESP Exome Variant Server reports R298H was observed in approximately 8/8,600 alleles (0.092%) from individuals of European background, indicating it is not a common benign variant in these populations. We interpret R298H as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083559	SCV000553758	likely benign	Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy	2025-01-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619912	SCV000736008	likely benign	Cardiovascular phenotype	2020-02-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768727	SCV000900097	likely benign	Cardiomyopathy	2020-04-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000786082	SCV001147733	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	ACTN2: BS1, BS2
Illumina Laboratory Services, 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224119	SCV003920303	uncertain significance	Dilated cardiomyopathy 1AA; Myopathy, congenital, with structured cores and z-line abnormalities; Myopathy, distal, 6, adult-onset, autosomal dominant	2021-03-30	criteria provided, single submitter	clinical testing	ACTN2 NM_001103.3 exon 10 p.Arg298His (c.893G>A): This variant has been reported in the literature in one individual with DCM, one with HCM, and three with features of LVNC (Pugh 2014 PMID:24503780, Miszalski-Jamka 2017 PMID:28798025, Mademont-Soler 2017 PMID:28771489). However, at least two of these individuals also carried additional variants of uncertain clinical significance in other cardiomyopathy genes (Pugh 2014 PMID:24503780, Miszalski-Jamka 2017 PMID:28798025). This variant is present in 0.08% (110/126584) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/1-236902618-G-A), including one homozygote. This variant is present in ClinVar (Variation ID:43951). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
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; http://gnomad.broadinstitute.org/), 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.
Clinical Genetics, Academic Medical Center	RCV000786082	SCV001924773	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000786082	SCV001927224	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000786082	SCV001957424	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549448	SCV004772366	likely benign	ACTN2-related disorder	2023-12-11	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).