ClinVar Miner

Submissions for variant NM_000478.6(ALPL):c.299C>T (p.Thr100Met) (rs1201942473)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
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 2020-10-03 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 100 of the ALPL protein (p.Thr100Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with hypophosphatasia (PMID: 31707452, 15660230, 26432670). It is also known as T83M in the literature. ClinVar contains an entry for this variant (Variation ID: 812034). This variant has been reported to affect ALPL protein function (PMID: 19500388). For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.