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NM_000478.6(ALPL):c.874C>T (p.Pro292Ser) AND not provided

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 7, 2022
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:
RCV002648134.3

Allele description [Variation Report for NM_000478.6(ALPL):c.874C>T (p.Pro292Ser)]

NM_000478.6(ALPL):c.874C>T (p.Pro292Ser)

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>T (p.Pro292Ser)
HGVS:
  • NC_000001.11:g.21573676C>T
  • NG_008940.2:g.69694C>T
  • NM_000478.5:c.874C>T
  • NM_000478.6:c.874C>TMANE SELECT
  • NM_001127501.4:c.709C>T
  • NM_001177520.3:c.643C>T
  • NM_001369803.2:c.874C>T
  • NM_001369804.2:c.874C>T
  • NM_001369805.2:c.874C>T
  • NP_000469.3:p.Pro292Ser
  • NP_001120973.2:p.Pro237Ser
  • NP_001170991.1:p.Pro215Ser
  • NP_001356732.1:p.Pro292Ser
  • NP_001356733.1:p.Pro292Ser
  • NP_001356734.1:p.Pro292Ser
  • NC_000001.10:g.21900169C>T
  • NG_008940.1:g.69312C>T
Protein change:
P215S
Molecular consequence:
  • NM_000478.6:c.874C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127501.4:c.709C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001177520.3:c.643C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369803.2:c.874C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369804.2:c.874C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369805.2:c.874C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003523177Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Nov 7, 2022) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia.

Tenorio J, Álvarez I, Riancho-Zarrabeitia L, Martos-Moreno GÁ, Mandrile G, de la Flor Crespo M, Sukchev M, Sherif M, Kramer I, Darnaude-Ortiz MT, Arias P, Gordo G, Dapía I, Martinez-Villanueva J, Gómez R, Iturzaeta JM, Otaify G, García-Unzueta M, Rubinacci A, Riancho JA, Aglan M, Temtamy S, et al.

Am J Med Genet A. 2017 Mar;173(3):601-610. doi: 10.1002/ajmg.a.37991. Epub 2017 Jan 27.

PubMed [citation]
PMID:
28127875
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003523177.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. 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: 15694177; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This missense change has been observed in individual(s) with hypophosphatasia (PMID: 28127875). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs765458125, gnomAD 0.004%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 292 of the ALPL protein (p.Pro292Ser).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024