Submissions for variant NM_000478.6(ALPL):c.500C>T (p.Thr167Met)

dbSNP: rs1408325840

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253034	SCV001428551	pathogenic	Adult hypophosphatasia	2018-04-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001879863	SCV002137391	pathogenic	not provided	2025-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 167 of the ALPL protein (p.Thr167Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 16583935, 25731960; internal data). This variant is also known as p.Thr150Met in TNSALP. ClinVar contains an entry for this variant (Variation ID: 975901). 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 ALPL protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001253034	SCV004193228	likely pathogenic	Adult hypophosphatasia	2023-12-06	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001879863	SCV004236151	pathogenic	not provided	2023-04-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782688	SCV005394569	pathogenic	Hypophosphatasia	2024-09-12	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.500C>T (p.Thr167Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250944 control chromosomes (gnomAD). c.500C>T has been reported in the literature in individuals affected with Hypophosphatasia (Ligutic_2005, Del Ange_2020, Rush_2021). 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 (Del Ange_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32160374, 16583935, 34633109). ClinVar contains an entry for this variant (Variation ID: 975901). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005014309	SCV005642367	pathogenic	Adult hypophosphatasia; Childhood hypophosphatasia; Infantile hypophosphatasia	2024-01-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001879863	SCV005894351	likely pathogenic	not provided	2025-01-01	criteria provided, single submitter	clinical testing	ALPL: PM1, PM2, PS4:Moderate, PS3:Supporting
PreventionGenetics, part of Exact Sciences	RCV004548107	SCV004734650	pathogenic	ALPL-related disorder	2024-02-22	no assertion criteria provided	clinical testing	The ALPL c.500C>T variant is predicted to result in the amino acid substitution p.Thr167Met. This variant in the heterozygous condition has been reported in one patient with adult-onset hypophosphatasia (HPP) (Braunstein. 2016. PubMed ID: 28326335). This variant has also been reported in one child with childhood HPP (Whyte et al. 2015. PubMed ID: 25731960). This variant, along with another missense variant in the ALPL gene, has been reported in an adult female with subtrochanteric and diaphyseal femoral fractures (Genest and Seefried. 2018. PubMed ID: 29774402). Functional studies suggest the p.Thr167Met variant led to reduced alkaline phosphatase activity (Table S3, Del Angel G et al 2020. PubMed ID: 32160374). The c.500C>T (p.Thr167Met) variant has not been observed in a public variant allele frequency database, indicating that this variant is rare. In summary, we consider this variant to be pathogenic.