Submissions for variant NM_001103.4(ACTN2):c.1864G>A (p.Asp622Asn)

gnomAD frequency: 0.00094  dbSNP: rs138452803

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036887	SCV000060542	likely benign	not specified	2015-01-29	criteria provided, single submitter	clinical testing	p.Asp622Asn in exon 16 of ACTN2: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (33/10562) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs138452803).
GeneDx	RCV001535412	SCV000235692	likely benign	not provided	2020-03-27	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31737537)
Ambry Genetics	RCV000253694	SCV000320251	likely benign	Cardiovascular phenotype	2018-06-01	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.
Illumina Laboratory Services, Illumina	RCV000315302	SCV000355938	uncertain significance	Dilated cardiomyopathy 1AA	2018-01-13	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.
Invitae	RCV000473724	SCV000563577	likely benign	Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy	2024-01-24	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769763	SCV000901185	benign	Cardiomyopathy	2020-04-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036887	SCV001362351	likely benign	not specified	2019-09-23	criteria provided, single submitter	clinical testing	Variant summary: ACTN2 c.1864G>A (p.Asp622Asn) results in a conservative amino acid change located in the Spectrin repeat domain (IPR002017) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 251418 control chromosomes. The observed variant frequency is approximately 9.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ACTN2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.1864G>A has been reported in the literature at-least once in sequencing studies of individuals affected with Hypertrophic Cardiomyopathy. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy (Jaaskelainen_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments of likely benign (n=3) and uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV001535412	SCV004009946	benign	not provided	2023-04-01	criteria provided, single submitter	clinical testing	ACTN2: BS1, BS2
Clinical Genetics, Academic Medical Center	RCV000036887	SCV001919707	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001535412	SCV001926603	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001535412	SCV001956155	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001535412	SCV001972193	likely benign	not provided		no assertion criteria provided	clinical testing