Submissions for variant NM_000478.6(ALPL):c.526G>A (p.Ala176Thr)

gnomAD frequency: 0.00016  dbSNP: rs121918019

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000014677	SCV000678013	likely pathogenic	Infantile hypophosphatasia	2014-01-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763299	SCV000893964	pathogenic	Adult hypophosphatasia; Childhood hypophosphatasia; Infantile hypophosphatasia	2022-05-10	criteria provided, single submitter	clinical testing
Invitae	RCV000808101	SCV000948193	pathogenic	not provided	2024-01-18	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 176 of the ALPL protein (p.Ala176Thr). This variant is present in population databases (rs121918019, gnomAD 0.02%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 10679946, 11438998, 18559907, 19232125, 25731960). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 13683). 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%. Experimental studies have shown that this missense change affects ALPL function (PMID: 10679946, 19500388). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000808101	SCV001250366	likely pathogenic	not provided	2022-06-01	criteria provided, single submitter	clinical testing	ALPL: PM2, PP3, PP4, PS3:Supporting, PS4:Supporting
Athena Diagnostics	RCV000808101	SCV001476897	likely pathogenic	not provided	2020-08-28	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Computational tools predict that this variant is damaging.
GeneDx	RCV000808101	SCV001819518	pathogenic	not provided	2022-11-23	criteria provided, single submitter	clinical testing	Observed in the compound heterozygous state with the R272C variant in two siblings with HPP; the parent who carried the A176T variant was noted to be tall without physical features of HPP or premature loss of deciduous teeth (Stevenson et al., 2008); Published functional studies demonstrate A176T reduces ALP activity (Fauvert et al., 2009; Taillandier et al., 2000); 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: 16769381, 34258332, 34662886, 19500388, 20089612, 10679946, 11855933, 11438998, 29160033, 28580391, 29774402, 27030892, 29160013, 15660230, 29236161, 29354166, 18559907, 34213743, 34426522, 34515659, 31589614, 33549410, 33299629, 35197081, 32160374)
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001275108	SCV001984852	pathogenic	Hypophosphatasia	2020-10-13	criteria provided, single submitter	clinical testing	This variant has been previously reported as single heterozygous variant or in combination with another ALPL alteration in patients with hypophosphatasia (PMID: 32811521, 21713987, 25731960, 10679946, 19500388, 11438998, 29354166, 19232125, 29236161). Experimental studies have shown that this missense change results in reduced enzymatic activity (PMID: 10679946, 19500388, 32160374). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0096% (27/282400) and thus is presumed to be rare. The c.526G>A (p.Ala176Thr) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. An in-frame deletion variant was detected in trans and has been previously reported as a compound heterozygous change in patients with hypophosphatasia (PMID:15660230). Based on the available evidence, the c.526G>A (p.Ala176Thr) variant is classified as Pathogenic.
Revvity Omics, Revvity	RCV000808101	SCV002023113	pathogenic	not provided	2020-12-30	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002276549	SCV002564783	pathogenic	Osteogenesis imperfecta	2021-11-30	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288490	SCV002581002	likely pathogenic	Adult hypophosphatasia	2022-06-30	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000014678	SCV003807060	pathogenic	Childhood hypophosphatasia	2022-11-11	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PM2 supporting, PM3 very strong, PP3 supporting, PP4
Baylor Genetics	RCV002288490	SCV004193676	pathogenic	Adult hypophosphatasia	2023-10-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549369	SCV004753140	pathogenic	ALPL-related disorder	2024-02-22	criteria provided, single submitter	clinical testing	The ALPL c.526G>A variant is predicted to result in the amino acid substitution p.Ala176Thr. This variant has been reported as a single heterozygous variant or in combination with another ALPL variant in both children and adults with hypophosphatasia (Reported as p.Ala159Thr, Taillandier et al. 2000. PubMed ID: 10679946; Taillandier et al. 2001. PubMed ID: 11438998; Fauvert et al. 2009. PubMed ID: 19500388; Reibel et al. 2009. PubMed ID: 19232125; Gagnon et al. 2010. PubMed ID: 20089612; Wenkert et al. 2011. PubMed ID: 21713987; Whyte et al. 2015. PubMed ID: 25731960; Vogt et al. 2020. PubMed ID: 32811521). Of note, in some cases mentioned above the c.526G>A (p.Ala176Thr) and other ALPL variant were confirmed to be in the compound heterozygous state, where in others phase was not determined. Functional studies have shown that this variant leads to reduced enzyme activity (Reported as p.Ala159Thr, Taillandier et al. 2000. PubMed ID: 10679946; Fauvert et al. 2009. PubMed ID: 19500388). In addition, this variant is interpreted as pathogenic in the ALPL Mutation Database (https://alplmutationdatabase.jku.at/table/) and as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/13683/). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic.
OMIM	RCV000014677	SCV000034932	pathogenic	Infantile hypophosphatasia	2008-09-01	no assertion criteria provided	literature only
OMIM	RCV000014678	SCV000034933	pathogenic	Childhood hypophosphatasia	2008-09-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001275108	SCV001459878	pathogenic	Hypophosphatasia	2020-09-16	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001275108	SCV001749799	not provided	Hypophosphatasia		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 11-16-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.