Submissions for variant NM_001103.4(ACTN2):c.616-3C>T

gnomAD frequency: 0.00001  dbSNP: rs111464645

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000467688	SCV000553768	uncertain significance	Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change falls in intron 6 of the ACTN2 gene. It does not directly change the encoded amino acid sequence of the ACTN2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs111464645, gnomAD 0.008%). This variant has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 412278). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779686	SCV000916416	likely benign	not specified	2018-01-22	criteria provided, single submitter	clinical testing	Variant summary: The ACTN2 c.616-3C>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 11/277060 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000079 (10/126592). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic ACTN2 variant (0.000025), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. In addition, one other clinical diagnostic laboratory classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign until more evidence becomes available.
GeneDx	RCV001702494	SCV001942980	likely benign	not provided	2019-07-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798842	SCV002042970	uncertain significance	Cardiomyopathy	2019-12-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002356709	SCV002654519	uncertain significance	Cardiovascular phenotype	2023-03-21	criteria provided, single submitter	clinical testing	The c.616-3C>T intronic variant results from a C to T substitution 3 nucleotides upstream from coding exon 7 in the ACTN2 gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000603027	SCV000733996	likely benign	Dilated cardiomyopathy 1AA		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000779686	SCV001920548	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702494	SCV001928428	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001702494	SCV001951238	likely benign	not provided		no assertion criteria provided	clinical testing