Submissions for variant NM_000478.6(ALPL):c.340G>A (p.Ala114Thr)

dbSNP: rs1320839573

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522077	SCV000617524	pathogenic	not provided	2022-09-09	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on enzyme activity (Del Angel et al., 2020); 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: 27274262, 28127875, 11547844, 29236161, 27149842, 32160374, 31400546, 35878747, 33069919, 34662886, 25731960)
Invitae	RCV000522077	SCV001580895	pathogenic	not provided	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 114 of the ALPL protein (p.Ala114Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 11547844; Invitae). This variant is also known as Ala97Thr. ClinVar contains an entry for this variant (Variation ID: 449399). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000709831	SCV003922681	likely pathogenic	Hypophosphatasia	2023-03-20	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.340G>A (p.Ala114Thr) 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 251012 control chromosomes (gnomAD). c.340G>A has been reported in the literature in individuals affected with Hypophosphatasia (Example: Del Angel_2020, Durrough_2021, Taillandier_2018, Tenorio_2017 and Whyte_2015, Pierpont_2021, Mumm_2001). At least one publication reports experimental evidence evaluating an impact on protein function and show severely decreased enzyme activity (Del Angel_2020). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003470650	SCV004194263	pathogenic	Adult hypophosphatasia	2023-10-11	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV000709831	SCV000840160	not provided	Hypophosphatasia		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.