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

gnomAD frequency: 0.00016  dbSNP: rs121918019

Total submissions: 20

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	2024-05-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000808101	SCV000948193	pathogenic	not provided	2025-01-15	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). 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: 10679946, 19500388). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000808101	SCV001250366	pathogenic	not provided	2024-09-01	criteria provided, single submitter	clinical testing	ALPL: PM1, PM2, PM5, PS4:Moderate, PP4, PS3: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	2024-07-18	criteria provided, single submitter	clinical testing	Published functional studies demonstrate A176T reduces ALP activity (PMID: 19500388, 10679946); 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 (PMID: 18559907); 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, 19500388, 20089612, 10679946, 11855933, 11438998, 29160033, 28580391, 29774402, 27030892, 29160013, 15660230, 29236161, 29354166, 34515659, 35197081, 36007526, 34662886, 34258332, 30576866, 33299629, 25731960, 34426522, 31589614, 32160374, 33549410, 34633109, 31707452, 30283912, 36361766, 36514157, 32811521, 18559907, 36444396, 19232125, 34213743)
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	2024-02-23	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001275108	SCV005399961	pathogenic	Hypophosphatasia	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative or loss of function are known mechanisms of disease in this gene and are associated with infantile, childhood, and adult hypophosphatasia (MIM# 241500, 241510, 146300 respectively) and odontohypophosphatasia (MIM#146300). Later-onset/mild disease is associated with dominant negative variants or loss of function variants that retain residual enzyme activity, while early-onset/severe disease is caused by more complete loss of function variants (PMID: 19500388, 20301329). (I) 0108 - This gene is associated with both recessive and dominant disease. Later-onset/mild disease has been reported with both autosomal dominant and recessive inheritance, while early-onset/severe disease is typically inherited in an autosomal recessive pattern (PMID: 19500388, 20301329). (I) 0112 - The condition associated with this gene has incomplete penetrance. Depending on the pathogenic variant, heterozygous carriers may be asymptomatic or have mild disease (PMID: 20301329). (I) 0115 - Variants in this gene are known to have variable expressivity. Variants associated with autosomal dominant disease may cause variable clinical symptoms in affected family members (PMID: 20301329). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (27 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated alkaline phosphatase domain (Pfam). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in many individuals in a heterozygous or compound heterozygous state, with disease ranging from infantile to adult onset hypophosphatasia (ClinVar, PMID: 19500388, 32811521, 31707452, 25731960). Disease severity is thought to be correlated with the second co-inherited pathogenic variant; individuals reported as heterozygous may have had an unidentified second pathogenic variant (PMID: 19500388). Unaffected carriers of this variant have also been reported (PMID: 18559907). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro functional assays show this variant results in approximately 30% residual enzyme activity, and does not act in a dominant negative manner (PMID: 19500388). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001275108	SCV005888145	pathogenic	Hypophosphatasia	2025-01-30	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.526G>A (p.Ala176Thr) results in a non-conservative amino acid change located in the Alkaline phosphatase domain (IPR001952) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 251038 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ALPL causing Hypophosphatasia (9.2e-05 vs 0.0035), allowing no conclusion about variant significance. c.526G>A has been reported in the literature in multiple individuals affected with Hypophosphatasia, including at-least 7 cases with a secondary pathogenic variant in ALPL and at-least one case with a single heterozygous A176T (example, Whyte_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 58% WT effect (Fauvert_2009). The following publications have been ascertained in the context of this evaluation (PMID: 25731960, 19500388). ClinVar contains an entry for this variant (Variation ID: 13683). Based on the evidence outlined above, the variant was classified 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.
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	RCV000808101	SCV004175131	likely pathogenic	not provided	2022-07-20	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549369	SCV004753140	pathogenic	ALPL-related disorder	2024-02-22	no assertion criteria provided	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.