Submissions for variant NM_020778.5(ALPK3):c.1382G>A (p.Gly461Asp)

gnomAD frequency: 0.00292  dbSNP: rs34409363

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000842957	SCV000984989	benign	not provided	2020-07-31	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26659599)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000842957	SCV001040377	benign	not provided	2025-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415969	SCV002717549	likely benign	Cardiovascular phenotype	2019-01-03	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003117615	SCV003800531	likely benign	Cardiomyopathy, familial hypertrophic 27	2024-10-25	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000842957	SCV005294189	benign	not provided		criteria provided, single submitter	not provided
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001700469	SCV005885774	likely benign	not specified	2025-02-10	criteria provided, single submitter	clinical testing	Variant summary: ALPK3 c.1382G>A (p.Gly461Asp) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 221364 control chromosomes, predominantly at a frequency of 0.0079 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.12 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALPK3 causing Cardiomyopathy phenotype (0.0071). To our knowledge, no occurrence of c.1382G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 682812). Based on the evidence outlined above, the variant was classified as likely benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001700469	SCV006070216	likely benign	not specified	2025-04-09	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV001700469	SCV001920141	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000842957	SCV001967483	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001700469	SCV001978172	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004538166	SCV004748780	benign	ALPK3-related disorder	2019-10-07	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).