Submissions for variant NM_000478.6(ALPL):c.532T>C (p.Tyr178His)

gnomAD frequency: 0.00001  dbSNP: rs1215600806

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001389955	SCV001591515	pathogenic	not provided	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 178 of the ALPL protein (p.Tyr178His). This variant is present in population databases (no rsID available, gnomAD 0.02%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 29160033, 31146036). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1076160). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ALPL function (PMID: 29160033, 31146036). For these reasons, this variant has been classified as Pathogenic.
Genomic Medicine Lab, University of California San Francisco	RCV002286432	SCV002576362	likely pathogenic	Micromelia		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003463033	SCV004191837	likely pathogenic	Adult hypophosphatasia	2023-10-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526122	SCV005040486	pathogenic	Hypophosphatasia	2024-03-01	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.532T>C (p.Tyr178His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251150 control chromosomes. c.532T>C has been reported in the literature in individuals affected with Hypophosphatasia. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. ClinVar contains an entry for this variant (Variation ID: 1076160). Based on the evidence outlined above, the variant was classified as pathogenic.