ClinVar Genomic variation as it relates to human health
NM_000478.6(ALPL):c.1250A>G (p.Asn417Ser)
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.1250A>G (p.Asn417Ser)
Variation ID: 13679 Accession: VCV000013679.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.12 1: 21576582 (GRCh38) [ NCBI UCSC ] 1: 21903075 (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 Mar 29, 2015 Oct 8, 2024 Jul 8, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000478.6:c.1250A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000469.3:p.Asn417Ser missense NM_001127501.4:c.1085A>G NP_001120973.2:p.Asn362Ser missense NM_001177520.3:c.1019A>G NP_001170991.1:p.Asn340Ser missense NM_001369803.2:c.1250A>G NP_001356732.1:p.Asn417Ser missense NM_001369804.2:c.1250A>G NP_001356733.1:p.Asn417Ser missense NM_001369805.2:c.1250A>G NP_001356734.1:p.Asn417Ser missense NC_000001.11:g.21576582A>G NC_000001.10:g.21903075A>G NG_008940.1:g.72218A>G P05186:p.Asn417Ser - Protein change
- N417S, N362S, N340S
- Other names
- N400S
- Canonical SPDI
- NC_000001.11:21576581: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.
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD) 0.00006
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
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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 |
1206 | 1222 |
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
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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 (1) |
no assertion criteria provided
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Oct 3, 2018 | RCV000014672.28 | |
Pathogenic (1) |
no assertion criteria provided
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Oct 15, 2001 | RCV000169778.2 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jul 8, 2024 | RCV000710510.23 | |
Pathogenic (2) |
criteria provided, single submitter
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Aug 5, 2019 | RCV001194283.2 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 28, 2024 | RCV001253058.5 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV004719646.1 | |
ALPL-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Jul 21, 2024 | RCV004739306.1 |
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
(Jan 25, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001405222.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 417 of the ALPL protein (p.Asn417Ser). … (more)
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 417 of the ALPL protein (p.Asn417Ser). This variant is present in population databases (rs121918014, gnomAD 0.006%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 11745997, 25731960, 27998428). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Asn400Ser. ClinVar contains an entry for this variant (Variation ID: 13679). 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: 19500388, 23688511). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 20, 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: SCV004563671.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The ALPL c.1250A>G; p.Asn417Ser variant (rs121918014) is reported in the literature in numerous heterozygous individuals affected with hypophosphatasia (Durrough 2021, Fauvert 2009, Hepp 2021, Taillandier … (more)
The ALPL c.1250A>G; p.Asn417Ser variant (rs121918014) is reported in the literature in numerous heterozygous individuals affected with hypophosphatasia (Durrough 2021, Fauvert 2009, Hepp 2021, Taillandier 2018), and in one compound heterozygous case affected with perinatal hypophosphatasia (Sergi 2001). This variant is also reported in ClinVar (Variation ID: 13679), and is found in the non-Finnish European population with an allele frequency of 0.006% (8/129126 alleles) in the Genome Aggregation Database. In vitro functional analyses demonstrate reduced ALP enzymatic activity and exhibits a dominant negative effect on wild-type enzymatic activity (Del Angel 2020, Fauvert 2009, Sultana 2013). Computational analyses also predict that this variant is deleterious (REVEL: 0.81). Based on available information, this variant is considered to be pathogenic. References: Del Angel G et al. Large-scale in vitro functional testing and novel variant scoring via protein modeling provide insights into alkaline phosphatase activity in hypophosphatasia. Hum Mutat. 2020 Jul;41(7):1250-1262. PMID: 32160374. Durrough C et al. Characterization of physical, functional, and cognitive performance in 15 adults with hypophosphatasia. Bone. 2021 Jan;142:115695. PMID: 33069919. Fauvert D et al. Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles. BMC Med Genet. 2009 Jun 6;10:51. PMID: 19500388. Hepp N et al. Biochemical, clinical and genetic characteristics in adults with persistent hypophosphatasaemia; Data from an endocrinological outpatient clinic in Denmark. Bone Rep. 2021 Jun 28;15:101101. PMID: 34258332. Sergi C et al. Perinatal hypophosphatasia: radiology, pathology and molecular biology studies in a family harboring a splicing mutation (648+1A) and a novel missense mutation (N400S) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. Am J Med Genet. 2001 Oct 15;103(3):235-40. PMID: 11745997. Sultana S et al. An asparagine at position 417 of tissue-nonspecific alkaline phosphatase is essential for its structure and function as revealed by analysis of the N417S mutation associated with severe hypophosphatasia. Mol Genet Metab. 2013 Jul;109(3):282-8. PMID: 23688511. Taillandier A et al. Genetic analysis of adults heterozygous for ALPL mutations. J Bone Miner Metab. 2018 Nov;36(6):723-733. PMID: 29236161. (less)
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Pathogenic
(Mar 28, 2024)
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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: SCV004194385.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Childhood hypophosphatasia
Affected status: yes
Allele origin:
germline
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Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital
Accession: SCV005326352.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
Comment:
The p.Asn417Ser variant detected in this individual is predicted to substitute the asparagine at amino acid position 417 with a serine in the crown domain … (more)
The p.Asn417Ser variant detected in this individual is predicted to substitute the asparagine at amino acid position 417 with a serine in the crown domain of the protein. The majority of in silico tools predict this variant is damaging, and functional studies have demonstrated that the p.Asn417Ser variant exerts a dominant negative effect on TNSALP, resulting in lack of dimer formation and reduced activity (PMID: 19500388, PMID: 236885113, PMID: 32160374). This variant is present in large population studies at low frequencies (50 of 1,613,808 alleles, no homozygotes, gnomAD v4.0.0). (less)
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Likely pathogenic
(Jul 17, 2018)
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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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Athena Diagnostics
Accession: SCV000840747.1
First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018 |
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Likely pathogenic
(Jul 16, 2015)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000332907.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Aug 05, 2019)
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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: SCV001363683.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: ALPL c.1250A>G (p.Asn417Ser) results in a conservative amino acid change located in the Crown domain (Simon-Bouy_2008) of the encoded protein sequence. Four of … (more)
Variant summary: ALPL c.1250A>G (p.Asn417Ser) results in a conservative amino acid change located in the Crown domain (Simon-Bouy_2008) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251442 control chromosomes (gnomAD). c.1250A>G has been reported in the literature as a single heterozygous variant (i.e. no other variants detected) in multiple individuals with features of mild HPP (odontohypophosphatasia, adult and childhood hypophosphatasia) but also in at least 2 parents that were carriers of the variant without any reported symptoms (Fauvert_2009, Reibel_2009, Whyte_2015). It has also been reported in compound heterozygous state with other pathogenic variants in patients affected with severe perinatal or severe childhood hypophosphatasia (Sergi_2001, Whyte_2015). These data indicate that the variant is very likely to be associated with disease. Using a cell system Fauvert et al reported that this variant has a dominant negative effect (Fauvert_2009) on wild-type enzymatic activity. In addition, Sultana et al performed several functional experiments using an in vitro system and concluded that a complete loss of ALP enzymatic activity resulting from the disruption of its functional dimer structure may represent the molecular basis of HPP associated with ALPL N417S (Sultana_2013). Three ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 25, 2021)
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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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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001711955.1
First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
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Likely pathogenic
(Nov 30, 2020)
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criteria provided, single submitter
Method: clinical testing
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Adult hypophosphatasia
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001428580.2
First in ClinVar: Aug 16, 2020 Last updated: Sep 25, 2021 |
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Pathogenic
(Feb 23, 2021)
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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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Revvity Omics, Revvity
Accession: SCV002018162.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jul 08, 2024)
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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: SCV001756506.4
First in ClinVar: Jul 24, 2021 Last updated: Sep 16, 2024 |
Comment:
Published functional studies demonstrate that N417S exhibits a dominant effect on the ALPL protein (PMID: 19500388); In silico analysis, which includes protein predictors and evolutionary … (more)
Published functional studies demonstrate that N417S exhibits a dominant effect on the ALPL protein (PMID: 19500388); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 34633109, 21956185, 29405932, 23688511, 11745997, 19500388, 27998428, 19232125, 28401263, 28939177, 29236161, 28000043, 29160013, 32160374, 28436937, 33069919, 25731960, 37993691, 36444396, 34258332, 33549410, 35878747, 34662886, 37422472) (less)
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Pathogenic
(Oct 15, 2001)
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no assertion criteria provided
Method: literature only
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HYPOPHOSPHATASIA, PERINATAL LETHAL
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034927.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 18, 2015 |
Comment on evidence:
For discussion of the asn400-to-ser (N400S) mutation in the ALPL gene that was found in compound heterozygous state in a fetus with peinatal lethal hypophosphatasia … (more)
For discussion of the asn400-to-ser (N400S) mutation in the ALPL gene that was found in compound heterozygous state in a fetus with peinatal lethal hypophosphatasia (see 241500) by Sergi et al. (2001), see 171760.0016. (less)
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Pathogenic
(Oct 03, 2018)
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no assertion criteria provided
Method: clinical testing
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Infantile hypophosphatasia
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000221154.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 23, 2019 |
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Pathogenic
(Jul 21, 2024)
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no assertion criteria provided
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: SCV005349953.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The ALPL c.1250A>G variant is predicted to result in the amino acid substitution p.Asn417Ser. This variant has been reported in multiple patients with autosomal dominant … (more)
The ALPL c.1250A>G variant is predicted to result in the amino acid substitution p.Asn417Ser. This variant has been reported in multiple patients with autosomal dominant or recessive hypophosphatasia, and also in patients with odontohypophosphatasia (Sergi et al. 2001. PubMed ID: 11745997; Fauvert et al. 2009. PubMed ID: 19500388; Sultana et al. 2013. PubMed ID: 23688511; Taillandier et al. 2017. PubMed ID: 29236161). Additionally, this variant was shown to confer ~5% enzyme activity compared to wild-type (Del Angel et al 2020. PubMed ID: 32160374). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
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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:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749798.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Pathogenic and reported on 11-16-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more)
Variant interpreted as Pathogenic and reported on 11-16-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Abnormal oral cavity morphology (present) , Abnormal muscle physiology (present)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-11-16
Testing laboratory interpretation: Pathogenic
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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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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 |
Efficacy of anti-sclerostin monoclonal antibody BPS804 in adult patients with hypophosphatasia. | Seefried L | The Journal of clinical investigation | 2017 | PMID: 28436937 |
Mutational and biochemical findings in adults with persistent hypophosphatasemia. | McKiernan FE | Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA | 2017 | PMID: 28401263 |
[Mutation analysis for two hypophosphatasia families with targeted next-generation sequencing]. | Bai Y | Zhonghua yi xue za zhi | 2016 | PMID: 27998428 |
Asfotase alfa therapy for children with hypophosphatasia. | Whyte MP | JCI insight | 2016 | PMID: 27699270 |
Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients. | Whyte MP | Bone | 2015 | PMID: 25731960 |
An asparagine at position 417 of tissue-nonspecific alkaline phosphatase is essential for its structure and function as revealed by analysis of the N417S mutation associated with severe hypophosphatasia. | Sultana S | Molecular genetics and metabolism | 2013 | PMID: 23688511 |
Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles. | Fauvert D | BMC medical genetics | 2009 | PMID: 19500388 |
Orodental phenotype and genotype findings in all subtypes of hypophosphatasia. | Reibel A | Orphanet journal of rare diseases | 2009 | PMID: 19232125 |
Hypophosphatasia: molecular testing of 19 prenatal cases and discussion about genetic counseling. | Simon-Bouy B | Prenatal diagnosis | 2008 | PMID: 18925618 |
Perinatal hypophosphatasia: radiology, pathology and molecular biology studies in a family harboring a splicing mutation (648+1A) and a novel missense mutation (N400S) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. | Sergi C | American journal of medical genetics | 2001 | PMID: 11745997 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ALPL | - | - | - | - |
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Text-mined citations for rs121918014 ...
HelpRecord last updated Oct 13, 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.