rs149889416
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong
The NM_000478.6(ALPL):c.1363G>A(p.Gly455Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,612,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G455D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000478.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALPL | NM_000478.6 | c.1363G>A | p.Gly455Ser | missense_variant | 12/12 | ENST00000374840.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALPL | ENST00000374840.8 | c.1363G>A | p.Gly455Ser | missense_variant | 12/12 | 1 | NM_000478.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152202Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000449 AC: 11AN: 245118Hom.: 0 AF XY: 0.0000374 AC XY: 5AN XY: 133648
GnomAD4 exome AF: 0.0000534 AC: 78AN: 1460286Hom.: 0 Cov.: 33 AF XY: 0.0000523 AC XY: 38AN XY: 726546
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74358
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | 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. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 30, 2023 | 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) - |
Infantile hypophosphatasia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 14, 2016 | - - |
Adult hypophosphatasia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 27, 2024 | - - |
Childhood hypophosphatasia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Hypophosphatasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 07, 2017 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at