Submissions for variant NM_000478.6(ALPL):c.529G>A (p.Ala177Thr)

gnomAD frequency: 0.00004  dbSNP: rs199669988

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000673035	SCV000798201	uncertain significance	Infantile hypophosphatasia	2018-03-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778223	SCV000914389	pathogenic	Hypophosphatasia	2018-12-07	criteria provided, single submitter	clinical testing	The ALPL c.529G>A (p.Ala177Thr) missense variant, also known as p.Ala160Thr, has been reported in at least five studies in which it was found in a homozygous state in one individual with hypophosphatasia and in a compound heterozygous state in six individuals, including one individual with a milder adult-onset form of the disease and five individuals with the more severe infantile- or childhood-onset form of the disease (Goseki-Sone et al. 1998; Orimo et al. 2001; Beck et al. 2009; Collmann et al. 2009; Nair et al. 2018). The parents of three of the individuals with the childhood-onset form were shown to carry the p.Ala177Thr variant in a heterozygous state; these individuals were described as healthy but exhibited reduced serum alkaline phosphatase activity (Orimo et al. 2001). The p.Ala177Thr variant was absent from 111 controls (Goseki-Sone et al. 1998) and is reported at a frequency of 0.00174 in the East Asian population of the Exome Aggregation Consortium. In vitro functional studies conducted in several different cell lines suggest that the p.Ala177Thr variant does not affect protein expression relative to wild type but does have a moderate effect on protein function (Orimo et al. 2001; Di Mauro et al. 2002; Orimo et al. 2008). Based on the collective evidence, the p.Ala177Thr variant is classified as pathogenic for hypophosphatasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000806323	SCV000946314	pathogenic	not provided	2024-01-16	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 177 of the ALPL protein (p.Ala177Thr). This variant is present in population databases (rs199669988, gnomAD 0.2%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 9452105, 11760847). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Ala160Thr. ClinVar contains an entry for this variant (Variation ID: 556961). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects ALPL function (PMID: 11760847, 12162492, 18455459). For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV002249400	SCV002517558	pathogenic	Adult hypophosphatasia	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271560	SCV002555844	likely benign	not specified	2022-06-13	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.529G>A (p.Ala177Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251080 control chromosomes (gnomAD v2.1). This frequency is not higher than the estimated maximum expected for a pathogenic variant in ALPL causing Hypophosphatasia (0.0035), allowing no conclusion about variant significance. However, the variant was reported in the Japanese with a much higher subpopulation frequency, ranging from 1-1.86%, including at least 3 reported homozygotes (in the jMorp and HGVD-Kyoto databases, and in Nagata_2020), suggesting that the variant could be a benign polymorphism. On the other hand, the variant c.529G>A (aka. Ala160Thr), has been reported in the literature in a patient affected with a mild form of adult-type hypophosphatasia (Goseki-Sone_1998), however this patient also carried a pathogenic variant, c.979T>C (p.Phe327Leu) which could potentially explain the phenotype. The variant was also reported in 3 compound heterozygous patient affected with the childhood form of the disease (Orimo_2001), and although these patients all had a (likely) pathogenic variant in trans, however the technology used for genotyping (i.e. SSCP) couldn't rule out the presence of other undetected variants, which could explain the more severe manifestations in these patients. In addition, a recent study reported 2 healthy, homozygous Japanese individuals, and although both of them had serum ALP activity levels somewhat lower relative to the average of non-carriers, their levels remained within the normal range (Nagata_2020). Several publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant resulted in a moderately decreased activity (~81-84% of WT; Orimo_2001, Del Angel_2020), or normal / elevated alkaline phosphatase activity, together with preserved in vitro mineralization (Di Mauro_2002, Orimo_2008). Five submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, partly without evidence for independent evaluation, and classified the variant as pathogenic (n=3) or VUS (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002531329	SCV003566782	uncertain significance	Inborn genetic diseases	2020-10-30	criteria provided, single submitter	clinical testing	The c.529G>A (p.A177T) alteration is located in exon 6 (coding exon 5) of the ALPL gene. This alteration results from a G to A substitution at nucleotide position 529, causing the alanine (A) at amino acid position 177 to be replaced by a threonine (T). Based on data from the Genome Aggregation Database (gnomAD) database, the ALPL c.529G>A alteration was observed in 0.01% (35/282450) of total alleles studied, with a frequency of 0.15% (30/19950) in the East Asian subpopulation. This variant, reported as 507G>A, was identified in a Japanese adult with hypophosphatasia and a second ALPL variant confirmed in trans (Goseki-Sone, 1998). It was also detected in three German children with hypophosphatasia (reported as p.A160T), each with a second ALPL variant confirmed in trans (Orimo, 2001). This amino acid position is not well conserved and threonine is a reference amino acid in several species. Functional studies in COS1 cells demonstrated a reduction in alkaline phosphatase activity to ~80% of wild type (Orimo, 2001; Orimo, 2008; Del Angel, 2020). The in silico prediction for the p.A177T alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV002249400	SCV004193764	uncertain significance	Adult hypophosphatasia	2022-10-03	criteria provided, single submitter	clinical testing
Department of Pediatrics, Samsung Medical Center, Samsung Medical Center	RCV001252803	SCV001163946	uncertain significance	Microcephaly		no assertion criteria provided	research