NM_000478.6(ALPL):c.874C>A (p.Pro292Thr) AND Hypophosphatasia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 13, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003317526.1

Allele description [Variation Report for NM_000478.6(ALPL):c.874C>A (p.Pro292Thr)]

NM_000478.6(ALPL):c.874C>A (p.Pro292Thr)

Gene:

ALPL:alkaline phosphatase, biomineralization associated [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.12

Genomic location:

Preferred name:

NM_000478.6(ALPL):c.874C>A (p.Pro292Thr)

HGVS:

NC_000001.11:g.21573676C>A
NG_008940.1:g.69312C>A
NM_000478.6:c.874C>AMANE SELECT
NM_001127501.4:c.709C>A
NM_001177520.3:c.643C>A
NM_001369803.2:c.874C>A
NM_001369804.2:c.874C>A
NM_001369805.2:c.874C>A
NP_000469.3:p.Pro292Thr
NP_001120973.2:p.Pro237Thr
NP_001170991.1:p.Pro215Thr
NP_001356732.1:p.Pro292Thr
NP_001356733.1:p.Pro292Thr
NP_001356734.1:p.Pro292Thr
NC_000001.10:g.21900169C>A
NM_000478.5:c.874C>A

Protein change:

P215T

Links:

dbSNP: rs765458125

NCBI 1000 Genomes Browser:

rs765458125

Molecular consequence:

NM_000478.6:c.874C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127501.4:c.709C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001177520.3:c.643C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369803.2:c.874C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369804.2:c.874C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369805.2:c.874C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypophosphatasia
Synonyms:: Phosphoethanol-aminuria
Identifiers:: MONDO: MONDO:0018570; MedGen: C0020630

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004020639	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jun 13, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15694177, 32160374, 32973344, 32811521 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004020639

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jun 13, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Characterization of 11 novel mutations in the tissue non-specific alkaline phosphatase gene responsible for hypophosphatasia and genotype-phenotype correlations.

Brun-Heath I, Taillandier A, Serre JL, Mornet E.

Mol Genet Metab. 2005 Mar;84(3):273-7. Epub 2004 Dec 19.

PubMed [citation]

PMID:: 15694177

Large-scale in vitro functional testing and novel variant scoring via protein modeling provide insights into alkaline phosphatase activity in hypophosphatasia.

Del Angel G, Reynders J, Negron C, Steinbrecher T, Mornet E.

Hum Mutat. 2020 Jul;41(7):1250-1262. doi: 10.1002/humu.24010. Epub 2020 Mar 18.

PubMed [citation]

PMID:: 32160374
PMCID:: PMC7317754

See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004020639.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: ALPL c.874C>A (p.Pro292Thr) 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 allele was found at a frequency of 8e-06 in 250868 control chromosomes (gnomAD). c.874C>A has been reported in the literature as a biallelic genotype in individuals affected with Hypophosphatasia, Autosomal Recessive (Brun-Heath_2005, Mornet_2021). These data indicate that the variant may be associated with disease. Enzyme activity assays using transiently transfected COS-1 and MDCK II cells have shown that the variant has 4% (Brun-Heath_2005) and 65% (Del Angel_2020) residual activity, respectively. The following publications have been ascertained in the context of this evaluation (PMID: 15694177, 32160374, 32973344, 32811521). Two ClinVar submitters have assessed the variant since 2014: both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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