Submissions for variant NM_020778.5(ALPK3):c.515T>G (p.Met172Arg)

gnomAD frequency: 0.00001  dbSNP: rs767791247

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001799966	SCV002044014	uncertain significance	not provided	2021-06-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001799966	SCV002185850	uncertain significance	not provided	2025-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 374 of the ALPK3 protein (p.Met374Arg). This variant is present in population databases (rs767791247, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ALPK3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1329658). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ALPK3 protein function with a positive predictive value of 80%. 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471166	SCV002768233	uncertain significance	Cardiomyopathy, familial hypertrophic 27	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hypertrophic cardiomyopathy 27 (MIM#618052). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 1 homozygote). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV004641697	SCV005136590	uncertain significance	Cardiovascular phenotype	2024-06-22	criteria provided, single submitter	clinical testing	The p.M374R variant (also known as c.1121T>G), located in coding exon 5 of the ALPK3 gene, results from a T to G substitution at nucleotide position 1121. The methionine at codon 374 is replaced by arginine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.