ClinVar Genomic variation as it relates to human health
NM_000478.6(ALPL):c.620A>C (p.Gln207Pro)
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.
Pathogenic(2); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000478.6(ALPL):c.620A>C (p.Gln207Pro)
Variation ID: 13666 Accession: VCV000013666.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.12 1: 21564188 (GRCh38) [ NCBI UCSC ] 1: 21890681 (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 14, 2024 Aug 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000478.6:c.620A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000469.3:p.Gln207Pro missense NM_000478.5:c.620A>C NM_001127501.4:c.455A>C NP_001120973.2:p.Gln152Pro missense NM_001177520.3:c.389A>C NP_001170991.1:p.Gln130Pro missense NM_001369803.2:c.620A>C NP_001356732.1:p.Gln207Pro missense NM_001369804.2:c.620A>C NP_001356733.1:p.Gln207Pro missense NM_001369805.2:c.620A>C NP_001356734.1:p.Gln207Pro missense NC_000001.11:g.21564188A>C NC_000001.10:g.21890681A>C NG_008940.1:g.59824A>C P05186:p.Gln207Pro - Protein change
- Q207P, Q130P, Q152P
- Other names
- Q190P
- Canonical SPDI
- NC_000001.11:21564187: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
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The frequency of the allele represented by this VCV record.
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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 |
1177 | 1192 |
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, single submitter
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- | RCV000014654.24 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 14, 2023 | RCV000224906.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 26, 2023 | RCV003230364.1 |
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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Likely pathogenic
(Aug 14, 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: SCV002273361.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gln207 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been observed in individuals with ALPL-related conditions (PMID: 32066479), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 13666). This variant is also known as p.Gln190Pro. This missense change has been observed in individual(s) with clinical features of hypophosphatasia (PMID: 1409720; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 207 of the ALPL protein (p.Gln207Pro). (less)
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Pathogenic
(May 06, 2016)
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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: SCV000281377.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Infantile hypophosphatasia
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073153.1
First in ClinVar: Feb 04, 2022 Last updated: Feb 04, 2022 |
Comment:
The missense variant p.Q207P in ALPL (NM_000478.6) ha been previously reported with autosomal recessive infantile hypophosphatasia (Henthron P et al). It has been submitted to … (more)
The missense variant p.Q207P in ALPL (NM_000478.6) ha been previously reported with autosomal recessive infantile hypophosphatasia (Henthron P et al). It has been submitted to ClinVar as Pathogenic. The p.Q207P variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.Q207P missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glutamine residue at codon 207 of ALPL is conserved in all mammalian species. The nucleotide c.620 in ALPL is predicted conserved by GERP++ and PhyloP across 100 vertebrates (less)
Clinical Features:
Pain (present) , Hashimoto thyroiditis (present) , Tachycardia (present) , Hyperhidrosis (present)
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Uncertain significance
(Apr 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003929000.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
Variant summary: ALPL c.620A>C (p.Gln207Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: ALPL c.620A>C (p.Gln207Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251116 control chromosomes. c.620A>C has been reported in the literature in a compound heterozygous individual affected with Perinatal Hypophosphatasia, Autosomal Recessive (Henthorn_1992) carrying an additional variant scored as VUS-possibly pathogenic by our lab. This patient had enzyme activity of <10% in fibroblasts (Fedde_1996). The following publications have been ascertained in the context of this evaluation (PMID: 8675582, 1409720). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic (n=3) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly 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, INFANTILE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034909.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 11, 2015 |
Comment on evidence:
For discussion of the gln190-to-pro (Q190P) mutation in the ALPL gene that was found in compound heterozygous state in a patient with infantile hypophosphatasia (241500) … (more)
For discussion of the gln190-to-pro (Q190P) 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 171760.0004. (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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Can we identify individuals with an ALPL variant in adults with persistent hypophosphatasaemia? | Tornero C | Orphanet journal of rare diseases | 2020 | PMID: 32066479 |
Aberrant properties of alkaline phosphatase in patient fibroblasts correlate with clinical expressivity in severe forms of hypophosphatasia. | Fedde KN | The Journal of clinical endocrinology and metabolism | 1996 | PMID: 8675582 |
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 |
Text-mined citations for rs121918004 ...
HelpRecord last updated Apr 06, 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.