Submissions for variant NM_001130004.2(ACTN1):c.959G>A (p.Arg320Gln)

dbSNP: rs1566606055

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001267467	SCV001445648	likely pathogenic	Inborn genetic diseases	2018-07-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003558781	SCV004297115	uncertain significance	not provided	2022-12-24	criteria provided, single submitter	clinical testing	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. 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 ACTN1 protein function. ClinVar contains an entry for this variant (Variation ID: 986185). This missense change has been observed in individual(s) with ACTN1-related conditions (PMID: 25949529). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 320 of the ACTN1 protein (p.Arg320Gln).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004594261	SCV005086237	likely pathogenic	Platelet-type bleeding disorder 15	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Loss of function (LoF) and gain of function (GoF) are reported mechanisms of disease in this gene and are associated with platelet-type bleeding disorder 15 (MIM#615193). LoF and GoF have been reported for missense variants (PMIDs: 23434115, 30351444, 26879394, 31365757). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Arg320Trp): 16 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and very highly conserved with a minor amino acid change. (I) 0600 - Variant is located in the annotated Spectrin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been classified once as likely pathogenic by a clinical diagnostic laboratory and has been reported in one individual with macrothrombocytes and a mild bleeding phenotype (ClinVar; PMID: 25949529). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. The p.(Arg320Gln) mutant construct transfected into HeLa cells demonstrated dramatically increased actin bundling ability in vitro compared to WT actinin-1 (PMID: 31365757). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
PreventionGenetics, part of Exact Sciences	RCV003918815	SCV004728350	uncertain significance	ACTN1-related disorder	2024-02-07	no assertion criteria provided	clinical testing	The ACTN1 c.959G>A variant is predicted to result in the amino acid substitution p.Arg320Gln. This variant was reported in two affected siblings with mild bleeding and macrothrombocytopenia (Table 2, Westbury et al 2015. PubMed ID: 25949529). This variant has not been reported in a large population database, indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.