Submissions for variant NM_020778.5(ALPK3):c.5012C>T (p.Ala1671Val)

gnomAD frequency: 0.00289  dbSNP: rs36002219

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000954293	SCV000717661	benign	not provided	2019-02-19	criteria provided, single submitter	clinical testing
Invitae	RCV000954293	SCV001100916	benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002350463	SCV002654175	benign	Cardiovascular phenotype	2018-12-29	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.
CeGaT Center for Human Genetics Tuebingen	RCV000954293	SCV004010392	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	ALPK3: BP4, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000608140	SCV004222982	likely benign	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: ALPK3 c.5012C>T (p.Ala1671Val) results in a non-conservative amino acid change located in the Alpha-type protein kinase, alpha-kinase domain of 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 0.0029 in 1614096 control chromosomes in the gnomAD database, including 11 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in ALPK3 causing Cardiomyopathy (0.0029 vs 0.0071), however the presence of homozygotes is evidence the variant is a benign polymorphism. To our knowledge, no occurrence of c.5012C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004530767	SCV004725063	likely benign	ALPK3-related disorder	2019-03-01	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Clinical Genetics, Academic Medical Center	RCV000608140	SCV001925279	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000608140	SCV001970642	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000608140	SCV001978319	benign	not specified		no assertion criteria provided	clinical testing