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

gnomAD frequency: 0.00001  dbSNP: rs1201942473

Total submissions: 6

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.
Invitae	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	2023-05-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003918644	SCV004734424	pathogenic	ALPL-related condition	2024-02-29	criteria provided, single submitter	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.