Submissions for variant NM_000478.6(ALPL):c.1363G>A (p.Gly455Ser)

gnomAD frequency: 0.00004  dbSNP: rs149889416

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411942	SCV000486970	likely pathogenic	Infantile hypophosphatasia	2016-09-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778967	SCV000915394	pathogenic	Hypophosphatasia	2017-09-07	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the ALPL c.1363G>A (p.Gly455Ser) missense variant has been reported in a compound heterozygous state in at least five individuals diagnosed with hypophosphatasia, including four with a mild form of the disease, and one with a perinatal lethal form (Draguet et al. 2004; Brun-Heath et al. 2007; Fauvert et al. 2009; Olech et al. 2016). The p.Gly455Ser variant was also identified in a heterozygous state in two reportedly unaffected fathers. The father of a severely affected patient had a serum alkaline phosphatase activity within normal limits. Control data are unavailable for this variant, which is reported at a frequency of 0.000102 in the European (non-Finnish) population of the Genome Aggregation Database. Transient expression studies in COS-7 cells revealed that compared to the wildtype protein, the p.Gly455Ser variant protein exhibited reduced expression at the cell membrane and was retained in the cytoplasm and Golgi, suggesting that the variant protein is unable to dimerize and undergo glycosylation (Brun-Heath et al. 2007). Site-directed mutagenesis studies showed that the variant, which is located in the vicinity of the active site, exhibited 71% of wildtype alkaline phosphatase activity (Brun-Heath et al. 2007). This is consistent with the finding that alkaline phosphatase activity in serum from the healthy individual who was heterozygous for the variant, was at the low end of the reference range (Olech et al. 2016). Based on the collective evidence, the p.Gly455Ser 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	RCV001045527	SCV001209386	pathogenic	not provided	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 455 of the ALPL protein (p.Gly455Ser). This variant is present in population databases (rs149889416, gnomAD 0.01%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 15135428, 17719863, 25731960, 25736332, 27179278). This variant is also known as G438S. ClinVar contains an entry for this variant (Variation ID: 371400). 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: 17719863). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001045527	SCV001804244	likely pathogenic	not provided	2023-01-30	criteria provided, single submitter	clinical testing	Published functional studies of residual alkaline phosphatase activity compared to wildtype yield inconsistent results (Brun-Heath et al., 2007; Fauvert et al., 2009; Cundy et al., 2015; Del Angel et al., 2020); 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: 17719863, 15135428, 27179278, 25736332, 18328985, 19500388, 25731960, 32160374, 31589614)
Genome-Nilou Lab	RCV001580493	SCV001810261	likely pathogenic	Childhood hypophosphatasia	2021-07-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470350	SCV004191859	likely pathogenic	Adult hypophosphatasia	2023-10-20	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001045527	SCV001554355	likely pathogenic	not provided		no assertion criteria provided	clinical testing	The ALPL p.Gly455Ser variant has been identified in multiple publications in association with hypophosphatasia (HPP). A case study of a stillborn patient with severe skeletal symptoms consistent with perinantal lethal HPP with compound heterozgyous mutations in the ALPL gene including the G455S variant inherited paternally and a R428P variant interited maternally; ALP enzymatic activity in serum of the father with the G455S variant was 50U/l (reference range: 40-150 U/l), suggesting normal enzyme activity however on the lower end (Olech_2016_PMID: 27179278). Another case study of a patient with progressive renal failure leading to bone pain and multiple fractures revealed that he was compound heterozygous for the G455S variant as well as a T117H ALPL variant. Functional studies of the G455S variant demonstrated normal enzymatic activity compared to wildtype which was then impaired when extracellular phosphate concentrations were increased; this change in phosphate concentration did not affect wildtype activity suggesting a genetic and environmental component to the phenotype (Cundy_2015_PMID: 25736332). A functional study by Brun-Health et al. (2007) showed abnormal cellular localization of the G455S ALPL mutant construct compared to wildtype (Brun-Heath_2007_PMID: 17719863). This variant was identified in 1/105 patients with HPP in the compound heterozygous state; the patient with this variant was determined to have mild childhood HPP (Whyte_2015_PMID: 25731960). The p.G455S variant was identified in dbSNP (ID: rs149889416) and in Clinvar (classified as likely pathogenic by Counsyl for infantile hypophosphatasia). The variant was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 11 of 245118 chromosomes at a frequency of 0.000045 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following population: European (non-Finnish) in 11 of 109950 chromosomes (freq: 0.0001); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. The p.Gly455 residue is conserved in mammals but not more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.