Submissions for variant NM_000478.6(ALPL):c.299C>T (p.Thr100Met)

gnomAD frequency: 0.00001  dbSNP: rs1201942473

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002604	SCV001160577	likely pathogenic	not specified	2019-05-21	criteria provided, single submitter	clinical testing	The ALPL c.299C>T; p.Thr100Met variant (rs1201942473) has been described in individuals with infantile and adult hypophosphatasia (Fauvert 2009, Maman 2016, Taillandier 2005). It is observed on only 2 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 100 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. In vitro analysis of the variant protein demonstrates very low (1.3%) residual activity compared to wildtype; in addition, these investigators showed evidence of a dominant-negative effect when the variant and wildtype proteins were co-expressed in Cos-1 cells (Fauvert 2009). Based on available information, this variant is considered likely pathogenic. REFERENCES Fauvert D et al. Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles. BMC Med Genet. 2009 Jun 6;10:51. Maman E et al. Atypical femoral fracture in a 51-year-old woman: Revealing a hypophosphatasia. Joint Bone Spine. 2016 May;83(3):346-8. Taillandier A et al. Molecular diagnosis of hypophosphatasia and differential diagnosis by targeted Next Generation Sequencing. Mol Genet Metab. 2015 Nov;116(3):215-20.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001382223	SCV001580894	pathogenic	not provided	2023-11-17	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 100 of the ALPL protein (p.Thr100Met). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 15660230, 26432670, 31707452). This variant is also known as T83M. ClinVar contains an entry for this variant (Variation ID: 812034). 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. Experimental studies have shown that this missense change affects ALPL function (PMID: 19500388). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV003229004	SCV003925776	pathogenic	Adult hypophosphatasia	2023-05-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001382223	SCV004009744	likely pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	ALPL: PM1, PS4:Moderate, PP4, PS3:Supporting
Baylor Genetics	RCV003229004	SCV004192983	pathogenic	Adult hypophosphatasia	2024-01-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001382223	SCV005201930	pathogenic	not provided	2024-01-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate significantly reduced enzyme activity in transfected cells and a dominant negative effect when co-transfected with wildtype ALPL (PMID: 32160374; 19500388); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19500388, 28436937, 34662886, 31707452, 32811521, 32973344, 26432670, 26992955, 37731773, 32160374)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782623	SCV005395654	pathogenic	Hypophosphatasia	2024-09-05	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.299C>T (p.Thr100Met) 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 allele was found at a frequency of 8e-06 in 250596 control chromosomes. c.299C>T has been reported in the literature in multiple compound heterozygous, heterozygous, and homozygous individuals affected with perinatal lethal, infantile, childhood, or adult forms of hypophosphatasia (e.g. delAngel_2020). These data indicate that the variant is very 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 enzyme activity in vitro (e.g. delAngel_2020). The following publication has been ascertained in the context of this evaluation (PMID: 32160374). ClinVar contains an entry for this variant (Variation ID: 812034). Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004553548	SCV004734424	pathogenic	ALPL-related disorder	2024-02-29	no assertion criteria provided	clinical testing	The ALPL c.299C>T variant is predicted to result in the amino acid substitution p.Thr100Met. This variant along with another ALPL variant was reported in a patient with adult hypophosphatasia (Maman et al. 2016. PubMed ID: 26992955). This variant in the compound heterozygous condition along with another ALPL variant was also reported in one patient with perinatal hypophosphatasia (Taillandier et al. 2015. PubMed ID: 26432670). This variant in the heterozygous condition was reported in one patient with childhood hypophosphatasia (Fauvert et al. 2009. PubMed ID: 19500388). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. Taken together, this variant is interpreted as pathogenic.