Published functional studies demonstrate a damaging effect on enzyme activity (Del Angel et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); 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: 27274262, 28127875, 11547844, 29236161, 27149842, 32160374, 31400546, 35878747, 33069919, 34662886, 25731960)
ClinVar Genomic variation as it relates to human health
NM_000478.6(ALPL):c.340G>A (p.Ala114Thr)
Germline
Classification
Help
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.
(5)
Help
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/Likely pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000478.6(ALPL):c.340G>A (p.Ala114Thr)
Variation ID: 449399 Accession: VCV000449399.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.12 1: 21563152 (GRCh38) [ NCBI UCSC ] 1: 21889645 (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 Dec 19, 2017 Jun 17, 2024 Feb 26, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000478.6:c.340G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000469.3:p.Ala114Thr missense NM_000478.5:c.340G>A NM_001127501.4:c.175G>A NP_001120973.2:p.Ala59Thr missense NM_001177520.3:c.109G>A NP_001170991.1:p.Ala37Thr missense NM_001369803.2:c.340G>A NP_001356732.1:p.Ala114Thr missense NM_001369804.2:c.340G>A NP_001356733.1:p.Ala114Thr missense NM_001369805.2:c.340G>A NP_001356734.1:p.Ala114Thr missense NC_000001.11:g.21563152G>A NC_000001.10:g.21889645G>A NG_008940.1:g.58788G>A - Protein change
- A114T, A37T, A59T
- Other names
- -
- Canonical SPDI
- NC_000001.11:21563151: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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Allele frequency
Help
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
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 |
1213 | 1229 | |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 18, 2023 | RCV000522077.9 | |
| Likely pathogenic (2) |
criteria provided, single submitter
|
Mar 20, 2023 | RCV000709831.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 26, 2024 | RCV003470650.2 |
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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|---|---|---|---|---|---|
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Pathogenic
(Sep 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000617524.3
First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect on enzyme activity (Del Angel et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); … (more)
Published functional studies demonstrate a damaging effect on enzyme activity (Del Angel et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); 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: 27274262, 28127875, 11547844, 29236161, 27149842, 32160374, 31400546, 35878747, 33069919, 34662886, 25731960) (less)
|
|
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Likely pathogenic
(Mar 20, 2023)
|
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: SCV003922681.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: ALPL c.340G>A (p.Ala114Thr) 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.340G>A (p.Ala114Thr) 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 was absent in 251012 control chromosomes (gnomAD). c.340G>A has been reported in the literature in individuals affected with Hypophosphatasia (Example: Del Angel_2020, Durrough_2021, Taillandier_2018, Tenorio_2017 and Whyte_2015, Pierpont_2021, Mumm_2001). At least one publication reports experimental evidence evaluating an impact on protein function and show severely decreased enzyme activity (Del Angel_2020). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
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Pathogenic
(Dec 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001580895.4
First in ClinVar: May 10, 2021 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 114 of the ALPL protein (p.Ala114Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 114 of the ALPL protein (p.Ala114Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 11547844; Invitae). This variant is also known as Ala97Thr. ClinVar contains an entry for this variant (Variation ID: 449399). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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Adult hypophosphatasia
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004194263.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
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not provided
(-)
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no classification provided
Method: phenotyping only
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Hypophosphatasia
Affected status: unknown
Allele origin:
paternal
|
GenomeConnect, ClinGen
Accession: SCV000840160.1
First in ClinVar: Oct 14, 2018 Last updated: Oct 14, 2018 |
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more)
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Prenatal maternal abnormality (present) , Short stature (present) , Abnormality of the parathyroid physiology (present) , Goiter (present) , Abnormality of the optic nerve (present) … (more)
Prenatal maternal abnormality (present) , Short stature (present) , Abnormality of the parathyroid physiology (present) , Goiter (present) , Abnormality of the optic nerve (present) , Myopia (present) , Tinnitus (present) , Depressivity (present) , Atrophic scars (present) , Joint hypermobility (present) , Abnormality of the intestine (present) , Abnormality of the stomach (present) , Feeding difficulties (present) (less)
Indication for testing: Diagnostic, Hypophosphatasia
Age: 10-19 years
Sex: male
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-09-18
Testing laboratory interpretation: Uncertain significance
|
Comment:
Comment:
Variant summary: ALPL c.340G>A (p.Ala114Thr) 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 was absent in 251012 control chromosomes (gnomAD). c.340G>A has been reported in the literature in individuals affected with Hypophosphatasia (Example: Del Angel_2020, Durrough_2021, Taillandier_2018, Tenorio_2017 and Whyte_2015, Pierpont_2021, Mumm_2001). At least one publication reports experimental evidence evaluating an impact on protein function and show severely decreased enzyme activity (Del Angel_2020). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 114 of the ALPL protein (p.Ala114Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 11547844; Invitae). This variant is also known as Ala97Thr. ClinVar contains an entry for this variant (Variation ID: 449399). 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%. For these reasons, this variant has been classified as Pathogenic.
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
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. |
Comment:
Published functional studies demonstrate a damaging effect on enzyme activity (Del Angel et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); 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: 27274262, 28127875, 11547844, 29236161, 27149842, 32160374, 31400546, 35878747, 33069919, 34662886, 25731960)
Comment:
Variant summary: ALPL c.340G>A (p.Ala114Thr) 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 was absent in 251012 control chromosomes (gnomAD). c.340G>A has been reported in the literature in individuals affected with Hypophosphatasia (Example: Del Angel_2020, Durrough_2021, Taillandier_2018, Tenorio_2017 and Whyte_2015, Pierpont_2021, Mumm_2001). At least one publication reports experimental evidence evaluating an impact on protein function and show severely decreased enzyme activity (Del Angel_2020). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 114 of the ALPL protein (p.Ala114Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 11547844; Invitae). This variant is also known as Ala97Thr. ClinVar contains an entry for this variant (Variation ID: 449399). 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%. For these reasons, this variant has been classified as Pathogenic.
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Impact of pediatric hypophosphatasia on behavioral health and quality of life. | Pierpont EI | Orphanet journal of rare diseases | 2021 | PMID: 33579333 |
| Characterization of physical, functional, and cognitive performance in 15 adults with hypophosphatasia. | Durrough C | Bone | 2021 | PMID: 33069919 |
| 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 |
| Molecular and cellular basis of hypophosphatasia. | Komaru K | Journal of oral biosciences | 2019 | PMID: 31400546 |
| Genetic analysis of adults heterozygous for ALPL mutations. | Taillandier A | Journal of bone and mineral metabolism | 2018 | PMID: 29236161 |
| 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 |
| Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients. | Whyte MP | Bone | 2015 | PMID: 25731960 |
| Hypophosphatasia: molecular diagnosis of Rathbun's original case. | Mumm S | Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research | 2001 | PMID: 11547844 |
Text-mined citations for rs1320839573 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.