rs1219494274
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000478.6(ALPL):āc.1010A>Gā(p.Asp337Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D337D) has been classified as Likely benign.
Frequency
Consequence
NM_000478.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALPL | NM_000478.6 | c.1010A>G | p.Asp337Gly | missense_variant | 10/12 | ENST00000374840.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALPL | ENST00000374840.8 | c.1010A>G | p.Asp337Gly | missense_variant | 10/12 | 1 | NM_000478.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251100Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135760
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727246
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 24, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2023 | 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. - |
Hypophosphatasia Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 14, 2023 | 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | May 06, 2021 | - - |
ALPL-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 14, 2023 | 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. - |
Adult hypophosphatasia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 04, 2023 | - - |
Infantile hypophosphatasia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 02, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at