ClinVar Genomic variation as it relates to human health
NM_000478.6(ALPL):c.529G>A (p.Ala177Thr)
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(3); Uncertain significance(3); Likely benign(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.529G>A (p.Ala177Thr)
Variation ID: 556961 Accession: VCV000556961.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.12 1: 21564097 (GRCh38) [ NCBI UCSC ] 1: 21890590 (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 Aug 5, 2018 May 1, 2024 Jan 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000478.6:c.529G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000469.3:p.Ala177Thr missense NM_001127501.4:c.364G>A NP_001120973.2:p.Ala122Thr missense NM_001177520.3:c.298G>A NP_001170991.1:p.Ala100Thr missense NM_001369803.2:c.529G>A NP_001356732.1:p.Ala177Thr missense NM_001369804.2:c.529G>A NP_001356733.1:p.Ala177Thr missense NM_001369805.2:c.529G>A NP_001356734.1:p.Ala177Thr missense NC_000001.11:g.21564097G>A NC_000001.10:g.21890590G>A NG_008940.1:g.59733G>A - Protein change
- A177T, A100T, A122T
- Other names
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- Canonical SPDI
- NC_000001.11:21564096:G:A
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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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0.00040 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
Exome Aggregation Consortium (ExAC) 0.00013
The Genome Aggregation Database (gnomAD), exomes 0.00013
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
- 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
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
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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
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
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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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Uncertain significance (1) |
criteria provided, single submitter
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Mar 8, 2018 | RCV000673035.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 7, 2018 | RCV000778223.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 16, 2024 | RCV000806323.6 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Oct 3, 2022 | RCV002249400.3 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 13, 2022 | RCV002271560.1 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001252803.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 30, 2020 | RCV002531329.2 |
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. |
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Uncertain significance
(Mar 08, 2018)
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criteria provided, single submitter
Method: clinical testing
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Infantile hypophosphatasia
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000798201.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Pathogenic
(Dec 07, 2018)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000914389.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The ALPL c.529G>A (p.Ala177Thr) missense variant, also known as p.Ala160Thr, has been reported in at least five studies in which it was found in a … (more)
The ALPL c.529G>A (p.Ala177Thr) missense variant, also known as p.Ala160Thr, has been reported in at least five studies in which it was found in a homozygous state in one individual with hypophosphatasia and in a compound heterozygous state in six individuals, including one individual with a milder adult-onset form of the disease and five individuals with the more severe infantile- or childhood-onset form of the disease (Goseki-Sone et al. 1998; Orimo et al. 2001; Beck et al. 2009; Collmann et al. 2009; Nair et al. 2018). The parents of three of the individuals with the childhood-onset form were shown to carry the p.Ala177Thr variant in a heterozygous state; these individuals were described as healthy but exhibited reduced serum alkaline phosphatase activity (Orimo et al. 2001). The p.Ala177Thr variant was absent from 111 controls (Goseki-Sone et al. 1998) and is reported at a frequency of 0.00174 in the East Asian population of the Exome Aggregation Consortium. In vitro functional studies conducted in several different cell lines suggest that the p.Ala177Thr variant does not affect protein expression relative to wild type but does have a moderate effect on protein function (Orimo et al. 2001; Di Mauro et al. 2002; Orimo et al. 2008). Based on the collective evidence, the p.Ala177Thr variant is classified as pathogenic for hypophosphatasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Adult hypophosphatasia
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002517558.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Likely benign
(Jun 13, 2022)
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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: SCV002555844.1
First in ClinVar: Aug 03, 2022 Last updated: Aug 03, 2022 |
Comment:
Variant summary: ALPL c.529G>A (p.Ala177Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: ALPL c.529G>A (p.Ala177Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251080 control chromosomes (gnomAD v2.1). This frequency is not higher than the estimated maximum expected for a pathogenic variant in ALPL causing Hypophosphatasia (0.0035), allowing no conclusion about variant significance. However, the variant was reported in the Japanese with a much higher subpopulation frequency, ranging from 1-1.86%, including at least 3 reported homozygotes (in the jMorp and HGVD-Kyoto databases, and in Nagata_2020), suggesting that the variant could be a benign polymorphism. On the other hand, the variant c.529G>A (aka. Ala160Thr), has been reported in the literature in a patient affected with a mild form of adult-type hypophosphatasia (Goseki-Sone_1998), however this patient also carried a pathogenic variant, c.979T>C (p.Phe327Leu) which could potentially explain the phenotype. The variant was also reported in 3 compound heterozygous patient affected with the childhood form of the disease (Orimo_2001), and although these patients all had a (likely) pathogenic variant in trans, however the technology used for genotyping (i.e. SSCP) couldn't rule out the presence of other undetected variants, which could explain the more severe manifestations in these patients. In addition, a recent study reported 2 healthy, homozygous Japanese individuals, and although both of them had serum ALP activity levels somewhat lower relative to the average of non-carriers, their levels remained within the normal range (Nagata_2020). Several publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant resulted in a moderately decreased activity (~81-84% of WT; Orimo_2001, Del Angel_2020), or normal / elevated alkaline phosphatase activity, together with preserved in vitro mineralization (Di Mauro_2002, Orimo_2008). Five submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, partly without evidence for independent evaluation, and classified the variant as pathogenic (n=3) or VUS (n=2). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain significance
(Oct 03, 2022)
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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: SCV004193764.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 16, 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: SCV000946314.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 177 of the ALPL protein (p.Ala177Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 177 of the ALPL protein (p.Ala177Thr). This variant is present in population databases (rs199669988, gnomAD 0.2%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 9452105, 11760847). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Ala160Thr. ClinVar contains an entry for this variant (Variation ID: 556961). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects ALPL function (PMID: 11760847, 12162492, 18455459). For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Oct 30, 2020)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003566782.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.529G>A (p.A177T) alteration is located in exon 6 (coding exon 5) of the ALPL gene. This alteration results from a G to A substitution … (more)
The c.529G>A (p.A177T) alteration is located in exon 6 (coding exon 5) of the ALPL gene. This alteration results from a G to A substitution at nucleotide position 529, causing the alanine (A) at amino acid position 177 to be replaced by a threonine (T). Based on data from the Genome Aggregation Database (gnomAD) database, the ALPL c.529G>A alteration was observed in 0.01% (35/282450) of total alleles studied, with a frequency of 0.15% (30/19950) in the East Asian subpopulation. This variant, reported as 507G>A, was identified in a Japanese adult with hypophosphatasia and a second ALPL variant confirmed in trans (Goseki-Sone, 1998). It was also detected in three German children with hypophosphatasia (reported as p.A160T), each with a second ALPL variant confirmed in trans (Orimo, 2001). This amino acid position is not well conserved and threonine is a reference amino acid in several species. Functional studies in COS1 cells demonstrated a reduction in alkaline phosphatase activity to ~80% of wild type (Orimo, 2001; Orimo, 2008; Del Angel, 2020). The in silico prediction for the p.A177T alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: research
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Microcephaly
Affected status: yes
Allele origin:
germline
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Department of Pediatrics, Samsung Medical Center, Samsung Medical Center
Accession: SCV001163946.1
First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020 |
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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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Estimation of the carrier frequencies and proportions of potential patients by detecting causative gene variants associated with autosomal recessive bone dysplasia using a whole-genome reference panel of Japanese individuals. | Nagaoka S | Human genome variation | 2021 | PMID: 33452237 |
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 |
Association of ALPL variants with serum alkaline phosphatase and bone traits in the general Japanese population: The Nagahama Study. | Nagata M | Journal of human genetics | 2020 | PMID: 31857675 |
Contribution of next generation sequencing in pediatric practice in Lebanon. A Study on 213 cases. | Nair P | Molecular genetics & genomic medicine | 2018 | PMID: 30293248 |
Molecular evolution of the tissue-nonspecific alkaline phosphatase allows prediction and validation of missense mutations responsible for hypophosphatasia. | Silvent J | The Journal of biological chemistry | 2014 | PMID: 25023282 |
How can calcium pyrophosphate crystals induce inflammation in hypophosphatasia or chronic inflammatory joint diseases? | Beck C | Rheumatology international | 2009 | PMID: 18821074 |
Neurosurgical aspects of childhood hypophosphatasia. | Collmann H | Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery | 2009 | PMID: 18769927 |
Functional assay of the mutant tissue-nonspecific alkaline phosphatase gene using U2OS osteoblast-like cells. | Orimo H | Molecular genetics and metabolism | 2008 | PMID: 18455459 |
Kinetic characterization of hypophosphatasia mutations with physiological substrates. | Di Mauro S | Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research | 2002 | PMID: 12162492 |
Mutational analysis and functional correlation with phenotype in German patients with childhood-type hypophosphatasia. | Orimo H | Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research | 2001 | PMID: 11760847 |
Hypophosphatasia: identification of five novel missense mutations (G507A, G705A, A748G, T1155C, G1320A) in the tissue-nonspecific alkaline phosphatase gene among Japanese patients. | Goseki-Sone M | Human mutation | 1998 | PMID: 9452105 |
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Text-mined citations for rs199669988 ...
HelpRecord last updated May 01, 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.