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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003523177	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 7, 2022)	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

SCV003523177

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 7, 2022)

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

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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).

#	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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