Submissions for variant NM_001103.4(ACTN2):c.686T>G (p.Leu229Trp)

gnomAD frequency: 0.00001  dbSNP: rs141793230

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000638625	SCV000760162	uncertain significance	Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy	2024-04-22	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 229 of the ACTN2 protein (p.Leu229Trp). This variant is present in population databases (rs141793230, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with ACTN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 532040). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACTN2 protein function with a positive predictive value of 80%. 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798936	SCV002042973	uncertain significance	Cardiomyopathy	2019-05-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477406	SCV002787734	uncertain significance	Dilated cardiomyopathy 1AA; Myopathy, congenital, with structured cores and z-line abnormalities; Myopathy, distal, 6, adult-onset, autosomal dominant	2021-09-15	criteria provided, single submitter	clinical testing