Submissions for variant NM_000478.6(ALPL):c.1190G>A (p.Gly397Asp)

gnomAD frequency: 0.00001  dbSNP: rs1400042777

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001756581	SCV001986031	uncertain significance	not provided	2019-08-26	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in nearby residues have been reported in association with hypophosphatasia in the Human Gene Mutation Database (Stenson et al., 2014).; This variant is associated with the following publications: (PMID: 28401263, 25731960)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001806253	SCV002051358	uncertain significance	not specified	2023-08-30	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.1190G>A (p.Gly397Asp) results in a non-conservative amino acid change located in the Crown domain (Xiao_2022) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. In addition, this variant disrupts the first nucleotide of exon 11, and therefore can affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251396 control chromosomes (i.e., 1 heterozygote; gnomAD v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1190G>A has been reported in the literature as a compound heterozygous genotype in at least one individual with mild childhood hypophosphatasia (e.g., Whyte_2015), as a non-informative genotype (second allele not specified) in one individual with odonto hypophosphatasia (e.g., Whyte_2015) and as a non-informative genotype (second allele not specified) in one adult with persistent hypophosphatasia (e.g., McKiernan_2017). These data do not allow any conclusion about variant significance in association with autosomal dominant or recessive disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25731960, 28401263, 35320273). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001756581	SCV003523201	pathogenic	not provided	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 397 of the ALPL protein (p.Gly397Asp). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 25731960, 28401263; Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 1303082). 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 disruptive. For these reasons, this variant has been classified as Pathogenic.