Submissions for variant NM_020778.5(ALPK3):c.62G>T (p.Gly21Val)

gnomAD frequency: 0.00011  dbSNP: rs1415475314

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001552915	SCV001773692	uncertain significance	not provided	2020-10-02	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32480058, 30847666)
Ambry Genetics	RCV002368572	SCV002665908	likely benign	Cardiovascular phenotype	2024-01-06	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001552915	SCV003026395	uncertain significance	not provided	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 223 of the ALPK3 protein (p.Gly223Val). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy or hypertrophic cardiomyopathy (PMID: 30847666, 32480058). ClinVar contains an entry for this variant (Variation ID: 1191731). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Clinical Genomics Laboratory, Stanford Medicine	RCV005401851	SCV006060736	uncertain significance	Cardiomyopathy	2022-10-31	criteria provided, single submitter	clinical testing	The p.Gly21Val variant in the ALPK3 gene has been previously reported in an individual with arrhythmogenic right ventricular cardiomyopathy (van Lint et al., 2019) and in an individual with hypertrophic cardiomyopathy (Herkert et al., 2020). This variant is also referred to as p.Gly223Val. This variant has been identified in 5/26,640 European (non-Finnish) chromosomes (6/78,034 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Notably, allele frequency information may be unreliable as this variant is indicated to have poor coverage. This variant is present in ClinVar (Accession: VCV001191731.10). The glycine at position 21 is not evolutionarily conserved. Computational tools predict that the p.Gly21Val variant does not impact protein function; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Gly21Val variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2; BP4]
Clinical Genetics, Academic Medical Center	RCV001552915	SCV001922859	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001552915	SCV001975867	uncertain significance	not provided		no assertion criteria provided	clinical testing