Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_001103.4(ACTN2):c.2276G>C(p.Arg759Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R759S) has been classified as Uncertain significance.
ACTN2 (HGNC:164): (actinin alpha 2) Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a muscle-specific, alpha actinin isoform that is expressed in both skeletal and cardiac muscles. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2013]
ACTN2 Gene-Disease associations (from GenCC):
intrinsic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Laboratory for Molecular Medicine, ClinGen
myopathy, congenital, with structured cores and z-line abnormalities
Our verdict: Uncertain_significance. The variant received 5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.871
PP5
Variant 1-236757607-G-C is Pathogenic according to our data. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236757607-G-C is described in CliVar as Pathogenic. Clinvar id is 189516.Status of the report is no_assertion_criteria_provided, 0 stars.