Submissions for variant NM_000478.6(ALPL):c.29T>C (p.Ile10Thr)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317753	SCV004020636	likely pathogenic	Hypophosphatasia	2023-06-06	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.29T>C (p.Ile10Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251484 control chromosomes (gnomAD). c.29T>C has been reported in the literature as a compound heterozygous genotype and at least once in the homozygous state in individuals affected with childhood/infantile-onset autosomal recessive Hypophosphatasia (e.g. Xu_2018, Mornet_2021). These data indicate that the variant may be associated with disease. A functional study examining the effect of the variant in vitro found that it results in 29% of WT activity but does not exhibit a dominant negative effect when expressed with the WT allele (del Angel_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32160374, 32973344, 29724887). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.