Submissions for variant NM_000478.6(ALPL):c.146A>G (p.Asn49Ser)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003870471	SCV004675316	pathogenic	not provided	2023-06-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn49 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 ALPL protein function. This missense change has been observed in individual(s) with clinical features of hypophosphatasia (Invitae). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 49 of the ALPL protein (p.Asn49Ser).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701857	SCV005204982	uncertain significance	not specified	2024-06-26	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.146A>G (p.Asn49Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251428 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.146A>G in individuals affected with Hypophosphatasia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 3013376). Based on the evidence outlined above, the variant was classified as uncertain significance.