NM_000478.6(ALPL):c.874C>A (p.Pro292Thr) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Aug 4, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001785916.8

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002021357	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 11, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002278516	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 4, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15694177, 28127875, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002021357

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 11, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002278516

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 4, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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

See all PubMed Citations (4)

Details of each submission

From Revvity Omics, Revvity, SCV002021357.3

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

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002278516.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 292 of the ALPL protein (p.Pro292Thr). This variant is present in population databases (rs765458125, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of hypophosphatasia (PMID: 15694177; Invitae). This variant is also known as P275T. ClinVar contains an entry for this variant (Variation ID: 1323883). 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. Experimental studies have shown that this missense change affects ALPL function (PMID: 15694177). This variant disrupts the p.Pro292 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28127875; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as 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

ClinVar

Relating variation to medicine