rs1553414611
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000478.6(ALPL):āc.1132G>Cā(p.Asp378His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D378V) has been classified as Pathogenic.
Frequency
Consequence
NM_000478.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALPL | NM_000478.6 | c.1132G>C | p.Asp378His | missense_variant | 10/12 | ENST00000374840.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALPL | ENST00000374840.8 | c.1132G>C | p.Asp378His | missense_variant | 10/12 | 1 | NM_000478.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461888Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727244
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 29, 2022 | Observed in heterozygyous state in a patient with benign prenatal hypophosphatasia (BP-HPP) in published literature (Wenkert et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35320273, 21713987) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 378 of the ALPL protein (p.Asp378His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with severe childhood hypophosphatasia (HPP) and adult HPP (PMID: 21713987). ClinVar contains an entry for this variant (Variation ID: 556746). 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%. This variant disrupts the p.Asp378 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1409720, 10508980, 17213282, 17922851, 19335222, 19500388, 21713987, 25731960, 28580391). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Adult hypophosphatasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 01, 2023 | - - |
Hypophosphatasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 15, 2023 | Variant summary: ALPL c.1132G>C (p.Asp378His) 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 was absent in 251492 control chromosomes (gnomAD). c.1132G>C has been reported as compound heterozygous in multiple individuals affected with Hypophosphatasia (Wenkert_2011, Whyte_2015, Kishani_2021, etc.). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Xiao_2022). However, missense variants in the same residue (D378G, D378Y, D378V) have been reported in the Human Gene Mutation Database in association with Hypophosphatasia and D378V has been classified as DV in our lab, supporting the functional importance of this residue of the protein. Three ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. The variant was classified as uncertain significance (n=1), likely pathogenic (n=1), and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Infantile hypophosphatasia Uncertain:1
Uncertain significance, flagged submission | clinical testing | Counsyl | Feb 15, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at