ClinVar Genomic variation as it relates to human health
NM_000478.6(ALPL):c.1403C>T (p.Ala468Val)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000478.6(ALPL):c.1403C>T (p.Ala468Val)
Variation ID: 427766 Accession: VCV000427766.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p36.12 1: 21577476 (GRCh38) [ NCBI UCSC ] 1: 21903969 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 10, 2017 Feb 20, 2024 Dec 5, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000478.6:c.1403C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000469.3:p.Ala468Val missense NM_001127501.4:c.1238C>T NP_001120973.2:p.Ala413Val missense NM_001177520.3:c.1172C>T NP_001170991.1:p.Ala391Val missense NM_001369803.2:c.1403C>T NP_001356732.1:p.Ala468Val missense NM_001369804.2:c.1403C>T NP_001356733.1:p.Ala468Val missense NM_001369805.2:c.1403C>T NP_001356734.1:p.Ala468Val missense NC_000001.11:g.21577476C>T NC_000001.10:g.21903969C>T NG_008940.1:g.73112C>T - Protein change
- A468V, A413V, A391V
- Other names
- -
- Canonical SPDI
- NC_000001.11:21577475:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
ALPL | - | - |
GRCh38 GRCh37 |
1181 | 1196 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Uncertain significance (1) |
no assertion criteria provided
|
- | RCV000490707.1 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 14, 2023 | RCV001380649.6 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 5, 2023 | RCV001805108.2 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 13, 2023 | RCV002464210.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Likely pathogenic
(Dec 04, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypophosphatasia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002050752.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
Variant summary: ALPL c.1403C>T (p.Ala468Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: ALPL c.1403C>T (p.Ala468Val) 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 8.2e-06 in 245090 control chromosomes. c.1403C>T has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with infantile onset Hypophosphatasia (example, Okawa_2019) and as a heterozygous genotype in one individual with adult onset Hypophosphatasia (HPP) (example, Talliandier_2018). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function (DelAngel_2020). The most pronounced variant effect results in <10% of normal TNSALP enzymatic activity reported as mutant activity relative to WT value of 0.039 (4%). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic citing an overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
|
Pathogenic
(Oct 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001578777.5
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 468 of the ALPL protein (p.Ala468Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 468 of the ALPL protein (p.Ala468Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hypophosphatasia (PMID: 31600233; Invitae). ClinVar contains an entry for this variant (Variation ID: 427766). 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. Experimental studies have shown that this missense change affects ALPL function (PMID: 32160374). This variant disrupts the p.Ala468 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12815606). 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. (less)
|
|
Pathogenic
(Dec 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Adult hypophosphatasia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV002759364.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Clinical Features:
Abnormality of the dentition (present) , Arthralgia (present) , Low alkaline phosphatase (present) , Abnormality of dental structure (present) , Fatigue (present) , Chronic pain … (more)
Abnormality of the dentition (present) , Arthralgia (present) , Low alkaline phosphatase (present) , Abnormality of dental structure (present) , Fatigue (present) , Chronic pain (present) (less)
|
|
Likely pathogenic
(Dec 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypophosphatasia
Affected status: yes
Allele origin:
germline
|
JKU Lab, Dept of Paediatrics, Johannes Kepler University
Accession: SCV004175731.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
GenomAD ƒ = 0.000193 (East Asian). Further information about the ACMG criteria applied can be looked up in the ALPL gene variant database. https://alplmutationdatabase.jku.at/
Comment on evidence:
Additional compound het c.[1403C>T];[319G>A], c.310G>A reported likely pathogenic in ClinVar.
|
|
Likely pathogenic
(Oct 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Adult hypophosphatasia
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004191948.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Likely pathogenic
(Jan 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004564272.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The ALPL c.1403C>T; p.Ala468Val variant (rs766656419) is reported in the literature in an individual with infantile-onset hypophosphatasia (HPP) that carried a second missense variant (Okawa … (more)
The ALPL c.1403C>T; p.Ala468Val variant (rs766656419) is reported in the literature in an individual with infantile-onset hypophosphatasia (HPP) that carried a second missense variant (Okawa 2019) and a heterozygous individual with symptoms of adult-onset HPP (Taillandier 2018). This variant is found in the general population with an overall allele frequency of 0.001% (3/276456 alleles) in the Genome Aggregation Database. The alanine at codon 468 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.944). Consistent with these predictions, functional assays show significantly reduced enzymatic activity of the variant protein (Del Angel 2020). Additionally, another variant at this codon (c.1402G>A; p.Ala468Thr) has been reported in homozygous individuals with HPP and is considered disease-causing (Spentchian 2003, Del Angel 2020). Based on available information, the p.Ala468Val variant is considered to be likely pathogenic. References: 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. Okawa R et al. Japanese nationwide survey of hypophosphatasia reveals prominent differences in genetic and dental findings between odonto and non-odonto types. PLoS One. 2019 Oct 10;14(10):e0222931. PMID: 31600233. Spentchian M et al. Severe hypophosphatasia: characterization of fifteen novel mutations in the ALPL gene. Hum Mutat. 2003 Jul;22(1):105-6. PMID: 12815606. Taillandier A et al. Genetic analysis of adults heterozygous for ALPL mutations. J Bone Miner Metab. 2018 Nov;36(6):723-733. PMID: 29236161. (less)
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
Low alkaline phosphatase
Affected status: unknown
Allele origin:
unknown
|
Institute of Human Genetics, University of Wuerzburg
Accession: SCV000579354.1
First in ClinVar: Jun 10, 2017 Last updated: Jun 10, 2017 |
|
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Hypophosphatasia: a genetic-based nosology and new insights in genotype-phenotype correlation. | Mornet E | European journal of human genetics : EJHG | 2021 | PMID: 32973344 |
Large-scale in vitro functional testing and novel variant scoring via protein modeling provide insights into alkaline phosphatase activity in hypophosphatasia. | Del Angel G | Human mutation | 2020 | PMID: 32160374 |
Japanese nationwide survey of hypophosphatasia reveals prominent differences in genetic and dental findings between odonto and non-odonto types. | Okawa R | PloS one | 2019 | PMID: 31600233 |
Genetic analysis of adults heterozygous for ALPL mutations. | Taillandier A | Journal of bone and mineral metabolism | 2018 | PMID: 29236161 |
Severe hypophosphatasia: characterization of fifteen novel mutations in the ALPL gene. | Spentchian M | Human mutation | 2003 | PMID: 12815606 |
Text-mined citations for rs766656419 ...
HelpRecord last updated Feb 28, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.