ClinVar Genomic variation as it relates to human health
NM_000478.6(ALPL):c.881A>C (p.Asp294Ala)
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
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NM_000478.6(ALPL):c.881A>C (p.Asp294Ala)
Variation ID: 13664 Accession: VCV000013664.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.12 1: 21573683 (GRCh38) [ NCBI UCSC ] 1: 21900176 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 11, 2015 Feb 20, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000478.6:c.881A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000469.3:p.Asp294Ala missense NM_001127501.4:c.716A>C NP_001120973.2:p.Asp239Ala missense NM_001177520.3:c.650A>C NP_001170991.1:p.Asp217Ala missense NM_001369803.2:c.881A>C NP_001356732.1:p.Asp294Ala missense NM_001369804.2:c.881A>C NP_001356733.1:p.Asp294Ala missense NM_001369805.2:c.881A>C NP_001356734.1:p.Asp294Ala missense NC_000001.11:g.21573683A>C NC_000001.10:g.21900176A>C NG_008940.1:g.69319A>C P05186:p.Asp294Ala - Protein change
- D294A, D217A, D239A
- Other names
- D277A
- Canonical SPDI
- NC_000001.11:21573682:A:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00004
The Genome Aggregation Database (gnomAD) 0.00007
Trans-Omics for Precision Medicine (TOPMed) 0.00008
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 | ||
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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. |
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ALPL | - | - |
GRCh38 GRCh37 |
1182 | 1197 |
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. |
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Pathogenic (1) |
no assertion criteria provided
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Oct 15, 1992 | RCV000014650.26 | |
Pathogenic (1) |
no assertion criteria provided
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Oct 15, 1992 | RCV000014651.28 | |
Pathogenic (2) |
criteria provided, single submitter
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Jun 23, 2023 | RCV000014652.21 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000224505.20 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 11, 2021 | RCV000589324.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 1, 2020 | RCV002276545.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 6, 2022 | RCV002496362.1 | |
ALPL-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Aug 29, 2022 | RCV004549362.1 |
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. |
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Pathogenic
(May 19, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hypophosphatasia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696804.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The ALPL c.881A>C (p.Asp294Ala) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant … (more)
Variant summary: The ALPL c.881A>C (p.Asp294Ala) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 2/119828 control chromosomes at a frequency of 0.0000167, which does not exceed the estimated maximal expected allele frequency of a pathogenic ALPL variant (0.0035355). The variant was found in multiple affected individuals with established dx hypophosphatasia with significantly reduced enzymatic activity. In addition, one reputable database classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Mar 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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Osteogenesis imperfecta
Affected status: unknown
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002564872.1
First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022 |
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Pathogenic
(Apr 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Adult hypophosphatasia
Infantile hypophosphatasia Childhood hypophosphatasia
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002786330.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Sep 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001875252.4
First in ClinVar: Sep 19, 2021 Last updated: Sep 14, 2023 |
Comment:
Retrospective study of twenty individuals heterozygous for p.(D294A) demonstrate the majority of subjects (18/20) had at least one or more HPP-associated finding defined as low … (more)
Retrospective study of twenty individuals heterozygous for p.(D294A) demonstrate the majority of subjects (18/20) had at least one or more HPP-associated finding defined as low alkaline phosphatase activity or clinical history associated with HPP, however, none had a previous clinical diagnosis (Tilden et al., 2020); Published in vitro functional studies of this variant (reported as D277A based on alternate nomenclature) indicate reduced alkaline phosphatase activity of the protein due to impaired protein folding and incorrect oligomerization (Fukushi-Irie et al., 2000); 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: 23509830, 19335222, 1409720, 30719581, 29659871, 11547844, 31707452, 18937943, 15694177, 25731960, 22397652, 32160374, 34000433, 32973344, 34125233, 33549410, 34515659, 10839996, 32803091, 34662886) (less)
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Pathogenic
(Aug 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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ALPL-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004114867.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The ALPL c.881A>C variant is predicted to result in the amino acid substitution p.Asp294Ala. This variant is also referred as p.Asp277Ala. This variant has been … (more)
The ALPL c.881A>C variant is predicted to result in the amino acid substitution p.Asp294Ala. This variant is also referred as p.Asp277Ala. This variant has been reported in compound heterozygous state in multiple individuals with hypophosphatasia (reported as p.Asp277Ala in Table 1, Henthorn et al. 1992. PubMed ID: 1409720; Whyte et al. 2012. PubMed ID: 22397652; Brun-Heath et al. 2004. PubMed ID: 15694177; https://alplmutationdatabase.jku.at/table/?). Functional studies show that this variant confers significantly reduced enzyme activity (Fukushi-Irié et al. 2000. PubMed ID: 10839996; Del Angel et al. 2020. PubMed ID: 32160374). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Oct 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypophosphatasia
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175350.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
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Pathogenic
(Jun 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Adult hypophosphatasia
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004195019.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(May 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226713.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3, PM3_very_strong, PS3_moderate, PS4
Number of individuals with the variant: 1
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Pathogenic
(Nov 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004564624.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The ALPL c.881A>C; p.Asp294Ala variant, also known as Asp277Ala in legacy nomenclature, is reported in the compound heterozygous state in several individuals with hypophosphatasia (Henthorn … (more)
The ALPL c.881A>C; p.Asp294Ala variant, also known as Asp277Ala in legacy nomenclature, is reported in the compound heterozygous state in several individuals with hypophosphatasia (Henthorn 1992, Sperelakis-Beedham 2021, Warren 2021). The variant is listed as pathogenic by several sources in the ClinVar database (Variation ID: 13664) and is reported in the general population with an overall allele frequency of 0.004% (12/282,262 alleles) in the Genome Aggregation Database. The amino acid at codon 294 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.946). In support of this prediction, functional studies show the variant protein has reduced alkaline phosphatase activity (Del Angel 2020, Fukushi-Irie 2000), folds improperly, and forms protein aggregates in the cell (Fukushi-Irie 2000). Based on available information, this variant is classified as pathogenic. References: Fukushi-Irie M et al. Possible interference between tissue-non-specific alkaline phosphatase with an Arg54-->Cys substitution and acounterpart with an Asp277-->Ala substitution found in a compound heterozygote associated with severe hypophosphatasia. Biochem J. 2000 Jun 15;348 Pt 3(Pt 3):633-42. PMID: 10839996. Henthorn PS et al. Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9924-8. PMID: 1409720. Sperelakis-Beedham B et al. Utility of genetic testing for prenatal presentations of hypophosphatasia. Mol Genet Metab. 2021 Mar;132(3):198-203. PMID: 33549410. Warren AM et al Bilateral atypical femoral fractures during denosumab therapy in a patient with adult-onset hypophosphatasia. Endocrinol Diabetes Metab Case Rep. 2021 Sep 1;2021:21-0096. PMID: 34515659. (less)
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Pathogenic
(Dec 30, 2014)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000280986.2
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
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Pathogenic
(Nov 30, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001832440.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021
Comment:
Patient analyzed with Comprehensive Skeletal Dysplasias and Disorders Panel
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Pathogenic
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001215060.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 294 of the ALPL protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 294 of the ALPL protein (p.Asp294Ala). This variant is present in population databases (rs121918002, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive hypophosphatasia (PMID: 1409720, 15694177, 19335222, 22397652, 25731960). This variant is also known as p.Asp277Ala. ClinVar contains an entry for this variant (Variation ID: 13664). 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: 10839996). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 15, 1992)
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no assertion criteria provided
Method: literature only
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HYPOPHOSPHATASIA, CHILDHOOD
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034906.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 11, 2015 |
Comment on evidence:
For discussion of the asp277-to-ala (D277A) mutation in the ALPL gene that was found in compound heterozygous state in a patient with infantile hypophosphatasia (241500) … (more)
For discussion of the asp277-to-ala (D277A) mutation in the ALPL gene that was found in compound heterozygous state in a patient with infantile hypophosphatasia (241500) by Henthorn et al. (1992), see 171760.0002. In 2 sibs with the mild childhood form of hypophosphatasia and in a 65-year-old woman with adult hypophosphatasia (146300), Henthorn et al. (1992) identified compound heterozygosity for 2 mutations in the ALPL gene: a D277A mutation, and 747G-A transition, resulting in a glu174-to-lys (E174K) substitution (171760.0008). (less)
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Pathogenic
(Oct 15, 1992)
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no assertion criteria provided
Method: literature only
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HYPOPHOSPHATASIA, ADULT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034907.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 11, 2015 |
Comment on evidence:
For discussion of the asp277-to-ala (D277A) mutation in the ALPL gene that was found in compound heterozygous state in a patient with infantile hypophosphatasia (241500) … (more)
For discussion of the asp277-to-ala (D277A) mutation in the ALPL gene that was found in compound heterozygous state in a patient with infantile hypophosphatasia (241500) by Henthorn et al. (1992), see 171760.0002. In 2 sibs with the mild childhood form of hypophosphatasia and in a 65-year-old woman with adult hypophosphatasia (146300), Henthorn et al. (1992) identified compound heterozygosity for 2 mutations in the ALPL gene: a D277A mutation, and 747G-A transition, resulting in a glu174-to-lys (E174K) substitution (171760.0008). (less)
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Pathogenic
(Oct 15, 1992)
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no assertion criteria provided
Method: literature only
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HYPOPHOSPHATASIA, INFANTILE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034905.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 11, 2015 |
Comment on evidence:
For discussion of the asp277-to-ala (D277A) mutation in the ALPL gene that was found in compound heterozygous state in a patient with infantile hypophosphatasia (241500) … (more)
For discussion of the asp277-to-ala (D277A) mutation in the ALPL gene that was found in compound heterozygous state in a patient with infantile hypophosphatasia (241500) by Henthorn et al. (1992), see 171760.0002. In 2 sibs with the mild childhood form of hypophosphatasia and in a 65-year-old woman with adult hypophosphatasia (146300), Henthorn et al. (1992) identified compound heterozygosity for 2 mutations in the ALPL gene: a D277A mutation, and 747G-A transition, resulting in a glu174-to-lys (E174K) substitution (171760.0008). (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Hypophosphatasia
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001459882.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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 |
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Not just a carrier: Clinical presentation and management of patients with heterozygous disease-causing alkaline phosphatase (ALPL) variants identified through expanded carrier screening. | Beck NM | Molecular genetics & genomic medicine | 2023 | PMID: 36444396 |
Exome sequencing and analysis of 454,787 UK Biobank participants. | Backman JD | Nature | 2021 | PMID: 34662886 |
Diagnostic utility of next-generation sequencing-based panel testing in 543 patients with suspected skeletal dysplasia. | Scocchia A | Orphanet journal of rare diseases | 2021 | PMID: 34627339 |
Bilateral atypical femoral fractures during denosumab therapy in a patient with adult-onset hypophosphatasia. | Warren AM | Endocrinology, diabetes & metabolism case reports | 2021 | PMID: 34515659 |
Utility of genetic testing for prenatal presentations of hypophosphatasia. | Sperelakis-Beedham B | Molecular genetics and metabolism | 2021 | PMID: 33549410 |
Hypophosphatasia: a genetic-based nosology and new insights in genotype-phenotype correlation. | Mornet E | European journal of human genetics : EJHG | 2021 | PMID: 32973344 |
Phenotypic Profiling in Subjects Heterozygous for 1 of 2 Rare Variants in the Hypophosphatasia Gene (ALPL). | Tilden DR | Journal of the Endocrine Society | 2020 | PMID: 32803091 |
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 |
Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients. | Whyte MP | Bone | 2015 | PMID: 25731960 |
Enzyme-replacement therapy in life-threatening hypophosphatasia. | Whyte MP | The New England journal of medicine | 2012 | PMID: 22397652 |
Chronic recurrent multifocal osteomyelitis mimicked in childhood hypophosphatasia. | Whyte MP | Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research | 2009 | PMID: 19335222 |
Characterization of 11 novel mutations in the tissue non-specific alkaline phosphatase gene responsible for hypophosphatasia and genotype-phenotype correlations. | Brun-Heath I | Molecular genetics and metabolism | 2005 | PMID: 15694177 |
Possible interference between tissue-non-specific alkaline phosphatase with an Arg54-->Cys substitution and acounterpart with an Asp277-->Ala substitution found in a compound heterozygote associated with severe hypophosphatasia. | Fukushi-Irié M | The Biochemical journal | 2000 | PMID: 10839996 |
Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia. | Henthorn PS | Proceedings of the National Academy of Sciences of the United States of America | 1992 | PMID: 1409720 |
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Text-mined citations for rs121918002 ...
HelpRecord last updated Jun 02, 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.