ClinVar Miner

Submissions for variant NM_020778.5(ALPK3):c.2181G>C (p.Glu727Asp)

gnomAD frequency: 0.00009  dbSNP: rs56191073
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478113 SCV000572998 likely benign not provided 2019-02-22 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000478113 SCV002332533 benign not provided 2025-01-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV002438181 SCV002747311 likely benign Cardiovascular phenotype 2020-12-29 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 RCV003114610 SCV003799674 benign Cardiomyopathy, familial hypertrophic 27 2022-03-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003479139 SCV004222980 uncertain significance not specified 2023-11-20 criteria provided, single submitter clinical testing Variant summary: ALPK3 c.2181G>C (p.Glu727Asp) results in a conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 251196 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in ALPK3 causing Cardiomyopathy (0.00027 vs 0.0071), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2181G>C 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.

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