ClinVar Genomic variation as it relates to human health
NM_000478.6(ALPL):c.512A>G (p.His171Arg)
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.512A>G (p.His171Arg)
Variation ID: 2202713 Accession: VCV002202713.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.12 1: 21564080 (GRCh38) [ NCBI UCSC ] 1: 21890573 (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 Feb 8, 2023 Feb 14, 2024 Feb 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000478.6:c.512A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000469.3:p.His171Arg missense NM_000478.5:c.512A>G NM_001127501.4:c.347A>G NP_001120973.2:p.His116Arg missense NM_001177520.3:c.281A>G NP_001170991.1:p.His94Arg missense NM_001369803.2:c.512A>G NP_001356732.1:p.His171Arg missense NM_001369804.2:c.512A>G NP_001356733.1:p.His171Arg missense NM_001369805.2:c.512A>G NP_001356734.1:p.His171Arg missense NC_000001.11:g.21564080A>G NC_000001.10:g.21890573A>G NG_008940.2:g.60098A>G - Protein change
- H116R, H171R, H94R
- Other names
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- Canonical SPDI
- NC_000001.11:21564079:A:G
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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
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Feb 6, 2024 | RCV002630053.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 1, 2023 | RCV003465995.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 26, 2023 | RCV003324080.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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
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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
(Jul 26, 2023)
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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: SCV004028720.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Variant summary: ALPL c.512A>G (p.His171Arg) 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.512A>G (p.His171Arg) 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 8e-06 in 251076 control chromosomes (i.e., 2 heterozygotes; gnomAD v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.512A>G has been reported in the literature in multiple compound heterozygous individuals affected with adult, odonto or infantile onset Hypophosphatasia (e.g., Mornet_2001, Larsen_2018, DelAngel_2020). The variant has also been reported in heterozygous individuals with low APL levels and other features of Hypophosphatasia, such as short stature and osteopenia (e.g, Riancho-Zarrabeitia_2016, Marini_2022, Gurevich_2020) These data indicate that the variant is very likely to be associated with autosomal recessive disease and may also cause autosomal dominant disease, but result in a milder phenotype in heterozygotes. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant displays approximately 4% enzymatic activity relative to wild type in vitro (e.g., DelAngel_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32160374, 30788858, 30202780, 34935951, 11395499, 26783040). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 01, 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: SCV004193128.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Feb 06, 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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004243415.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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Pathogenic
(Dec 26, 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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Invitae
Accession: SCV003523174.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 171 of the ALPL protein (p.His171Arg). … (more)
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 171 of the ALPL protein (p.His171Arg). This variant is present in population databases (rs778232217, gnomAD 0.007%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 26783040, 28127875, 32160374). ClinVar contains an entry for this variant (Variation ID: 2202713). 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). This variant disrupts the p.His171 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been observed in individuals with ALPL-related conditions (PMID: 10094560), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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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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ALPL Genotypes in Patients With Atypical Femur Fractures or Other Biochemical and Clinical Signs of Hypophosphatasia. | Marini F | The Journal of clinical endocrinology and metabolism | 2022 | PMID: 34935951 |
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 |
High prevalence of hypophosphatasia in Southern Israel. | Gurevich E | Acta paediatrica (Oslo, Norway : 1992) | 2020 | PMID: 30788858 |
Repeatedly low plasma alkaline phosphatase in a 56-year-old woman. A case of hypophosphatasia diagnosed in adulthood. | Larsen PB | Practical laboratory medicine | 2018 | PMID: 30202780 |
Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia. | Tenorio J | American journal of medical genetics. Part A | 2017 | PMID: 28127875 |
Clinical, biochemical and genetic spectrum of low alkaline phosphatase levels in adults. | Riancho-Zarrabeitia L | European journal of internal medicine | 2016 | PMID: 26783040 |
Structural evidence for a functional role of human tissue nonspecific alkaline phosphatase in bone mineralization. | Mornet E | The Journal of biological chemistry | 2001 | PMID: 11395499 |
Characterization of eleven novel mutations (M45L, R119H, 544delG, G145V, H154Y, C184Y, D289V, 862+5A, 1172delC, R411X, E459K) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in patients with severe hypophosphatasia. Mutations in brief no. 217. Online. | Taillandier A | Human mutation | 1999 | PMID: 10094560 |
Text-mined citations for this variant ...
HelpRecord last updated Feb 14, 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.