Submissions for variant NM_000478.6(ALPL):c.1010A>G (p.Asp337Gly)

dbSNP: rs1219494274

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668539	SCV000793160	uncertain significance	Infantile hypophosphatasia	2017-08-02	criteria provided, single submitter	clinical testing
Invitae	RCV001066978	SCV001232004	pathogenic	not provided	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 337 of the ALPL protein (p.Asp337Gly). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 25731960; Invitae). ClinVar contains an entry for this variant (Variation ID: 553154). 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: 32160374). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004547840	SCV004116807	likely pathogenic	ALPL-related disorder	2023-04-14	criteria provided, single submitter	clinical testing	The ALPL c.1010A>G variant is predicted to result in the amino acid substitution p.Asp337Gly. This variant in the heterozygous condition along with a second missense variant was reported in one patients with hypophosphatasia (Whyte et al. 2015. PubMed ID: 25731960; https://alplmutationdatabase.jku.at/table/). Functional studies suggest that p.Asp337Gly led to reduced enzyme activity (Table S1, Del Angel et al 2020. PubMed ID: 32160374). At PreventionGenetics this variant was detected in four patients undergoing ALPL sequencing, being heterozygous in three patients without a second variant, and in one patient along with a second heterozygous likely pathogenic ALPL variant. This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-21902238-A-G). In summary, this variant is interpreted as likely pathogenic.
Baylor Genetics	RCV003472101	SCV004194886	likely pathogenic	Adult hypophosphatasia	2023-08-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001829847	SCV004241450	likely pathogenic	Hypophosphatasia	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.1010A>G (p.Asp337Gly) 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 allele was found at a frequency of 4e-06 in 251100 control chromosomes (gnomAD). c.1010A>G has been reported in the literature in compound heterozygous state together with a second pathogenic variant in an individual affected with severe childhood-onset Hypophosphatasia (Whyte_2015). At least one publication reports experimental evidence evaluating an impact on protein function and demonstrated that the variant protein had a severely decreased activity (Del Angel_2020). The following publications have been ascertained in the context of this evaluation (PMID: 25731960, 34633109, 32160374, 37422472). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001066978	SCV004565141	likely pathogenic	not provided	2023-05-24	criteria provided, single submitter	clinical testing	The ALPL c.1010A>G; p.Asp337Gly variant (rs1219494274) is reported in the literature in one individual with severe childhood hypophosphatasia (HPP) that also carried a second missense variant (Whyte 2015). This variant is also reported in ClinVar (Variation ID: 553154) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Functional analyses of the variant protein show reduced enzyme activity (Del Angel 2020). Computational analyses predict that this variant is deleterious (REVEL: 0.964). Based on the available information, this variant is considered to be likely pathogenic. References: Whyte MP et al. Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients. Bone. 2015 Jun;75:229-39. PMID: 25731960. Del Angel G et al. Large-scale in vitro functional testing and novel variant scoring via protein modeling provide insights into alkaline phosphatase activity in hypophosphatasia. Hum Mutat. 2020 Jul;41(7):1250-1262. PMID: 32160374.
Natera, Inc.	RCV001829847	SCV002094084	uncertain significance	Hypophosphatasia	2021-05-06	no assertion criteria provided	clinical testing