Submissions for variant NM_000478.6(ALPL):c.346G>A (p.Ala116Thr)

dbSNP: rs121918013

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169426	SCV000220835	likely pathogenic	Infantile hypophosphatasia	2014-10-24	criteria provided, single submitter	literature only
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224118	SCV000280959	pathogenic	not provided	2016-01-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000224118	SCV000322323	pathogenic	not provided	2022-05-13	criteria provided, single submitter	clinical testing	Indentified in individuals with severe childhood hypophosphatasia and lethal hypophosphatasia, who also had a second variant in the ALPL gene (Whyte et al., 2015; Tailandier et al., 2001); Published functional studies demonstrate that A116T results in decreased alkaline phosphatase activity via a dominant-negative effect (Lia-Baldini et al., 2001; Foster et al., 2015); 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: 12920074, 25716980, 21168482, 19500388, 10679946, 10872988, 26590809, 28663156, 29236161, 32160374, 11438998, 33160095, 33069919, 34164522, 11479741, 25731960, 27535533)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590781	SCV000696799	pathogenic	Hypophosphatasia	2019-10-28	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.346G>A (p.Ala116Thr) 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 251048 control chromosomes (gnomAD). c.346G>A has been reported in the literature in multiple individuals affected with Hypophosphatasia (Hu_2000, Herasse_2003, Whyte_2015). These data indicate that the variant is very likely to be associated with disease. In vitro studies show that this variant leads to severely reduced alkaline phosphatase activity, also showing a weak dominant negative effect when co-expressed with the wild-type enzyme (Lia-Baldini_2001, Fauvert_2009, Ishida_2011) with consistent finding by an in vivo mouse model study (Foster_2011). Four ClinVar submissions (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000224118	SCV000706403	pathogenic	not provided	2017-03-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000224118	SCV000939644	pathogenic	not provided	2025-01-13	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 116 of the ALPL protein (p.Ala116Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypophosphatasias (PMID: 10679946, 10872988, 11438998, 12920074, 25731960). It has also been observed to segregate with disease in related individuals. This variant is also known as A94T and A99T. ClinVar contains an entry for this variant (Variation ID: 13677). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ALPL protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ALPL function (PMID: 21168482, 25716980). For these reasons, this variant has been classified as Pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000014669	SCV003932295	pathogenic	Adult hypophosphatasia	2023-02-06	criteria provided, single submitter	clinical testing	PS3, PS4, PM2, PP3
Baylor Genetics	RCV000014669	SCV004194452	pathogenic	Adult hypophosphatasia	2024-03-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224118	SCV005891463	pathogenic	not provided	2025-02-01	criteria provided, single submitter	clinical testing	ALPL: PS4, PM1, PP4:Moderate, PS3:Moderate, PM2:Supporting, PP3
OMIM	RCV000014668	SCV000034923	pathogenic	Childhood hypophosphatasia	2003-08-01	no assertion criteria provided	literature only
OMIM	RCV000014669	SCV000034924	pathogenic	Adult hypophosphatasia	2003-08-01	no assertion criteria provided	literature only
OMIM	RCV000014670	SCV000034925	pathogenic	Odontohypophosphatasia	2003-08-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000590781	SCV001459874	pathogenic	Hypophosphatasia	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549367	SCV004721383	pathogenic	ALPL-related disorder	2024-02-28	no assertion criteria provided	clinical testing	The ALPL c.346G>A variant is predicted to result in the amino acid substitution p.Ala116Thr. This variant has been documented to be causative for both autosomal dominant and autosomal recessive hypophosphatasia (HPP), and functional studies support its pathogenicity (see examples: Hu et al. 2000. PubMed ID: 10872988; Taillandier et al. 2001. PubMed ID: 11438998; Herasse et al. 2003. PubMed ID: 12920074; Fauvert et al. 2009. PubMed ID: 19500388; Ishida et al. 2011. PubMed ID: 21168482). This variant is also referred to as p.Ala99Thr in the literature. This variant has not been reported in a large population database, indicating this variant is rare. This variant is classified as pathogenic.