Submissions for variant NM_020778.5(ALPK3):c.1676C>T (p.Thr559Met)

gnomAD frequency: 0.00181  dbSNP: rs16974569

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000434029	SCV000525733	benign	not specified	2016-11-22	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000968863	SCV001116345	benign	not provided	2025-02-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002446694	SCV002736262	benign	Cardiovascular phenotype	2019-03-14	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003758769	SCV004564708	benign	Cardiomyopathy, familial hypertrophic 27	2023-11-11	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000968863	SCV005294191	benign	not provided		criteria provided, single submitter	not provided
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000434029	SCV005886088	benign	not specified	2025-02-10	criteria provided, single submitter	clinical testing	Variant summary: ALPK3 c.1676C>T (p.Thr559Met) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0066 in 241834 control chromosomes, predominantly at a frequency of 0.059 within the East Asian subpopulation in the gnomAD database, including 36 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 8 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.1676C>T 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: 384731). Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV004533033	SCV004737637	benign	ALPK3-related disorder	2019-04-09	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).