Submissions for variant NM_020778.5(ALPK3):c.904C>A (p.Leu302Met)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002392199	SCV002703622	uncertain significance	Cardiovascular phenotype	2024-06-07	criteria provided, single submitter	clinical testing	The c.1510C>A (p.L504M) alteration is located in exon 5 (coding exon 5) of the ALPK3 gene. This alteration results from a C to A substitution at nucleotide position 1510, causing the leucine (L) at amino acid position 504 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003095266	SCV003513528	uncertain significance	not provided	2024-06-29	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 504 of the ALPK3 protein (p.Leu504Met). This variant is not present in population databases (gnomAD no frequency). 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: 1774197). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Clinical Genomics Laboratory, Stanford Medicine	RCV003985028	SCV004801299	uncertain significance	Cardiomyopathy, familial hypertrophic 27	2021-05-07	criteria provided, single submitter	clinical testing	• The p.Leu504Met variant in the ALPK3 gene has not been previously reported in association with disease. • This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). • Computational tools predict that the p.Leu504Met 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.Leu504Met variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2; BP4]