Submissions for variant NM_020778.5(ALPK3):c.2177A>G (p.Gln726Arg)

gnomAD frequency: 0.01836  dbSNP: rs78778733

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000422981	SCV000528002	benign	not specified	2016-10-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000960877	SCV001107905	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002436305	SCV002751701	benign	Cardiovascular phenotype	2018-12-19	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000422981	SCV004122479	benign	not specified	2023-10-31	criteria provided, single submitter	clinical testing	Variant summary: ALPK3 c.2177A>G (p.Gln726Arg) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0049 in 251216 control chromosomes, predominantly at a frequency of 0.062 within the African or African-American subpopulation in the gnomAD database, including 32 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALPK3 causing Cardiomyopathy phenotype (0.0071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.2177A>G in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003758771	SCV004564653	benign	Cardiomyopathy, familial hypertrophic 27	2023-11-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004533063	SCV004736809	benign	ALPK3-related disorder	2019-08-15	criteria provided, single submitter	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).
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000960877	SCV001800636	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000422981	SCV001920855	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000422981	SCV001970521	benign	not specified		no assertion criteria provided	clinical testing