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

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 22, 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:: RCV003388160.1

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)

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

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Tssr69456 AND (alive[prop]) (0)
Gene
LSS lanosterol synthase [Homo sapiens]
LSS lanosterol synthase [Homo sapiens]
Gene ID:4047

Gene
4047[uid] AND (alive[prop]) (1)
Gene
INM1 inositol monophosphate 1-phosphatase INM1 [Saccharomyces cerevisiae S288C]
INM1 inositol monophosphate 1-phosphatase INM1 [Saccharomyces cerevisiae S288C]
Gene ID:856442

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004100077	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Sep 22, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004100077

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Sep 22, 2023)

germline

clinical testing

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

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

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

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004100077.1

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

Description

Variant summary: ALPL c.874C>T (p.Pro292Ser) 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 4e-06 in 250868 control chromosomes (gnomAD). c.874C>T has been reported in the literature as a compound heterozygous genotype in trans with a pathogenic variant in three siblings affected with perinatal autosomal recessive Hypophosphatasia and segregated with the disease phenotype in this family (Tenorio_2017). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, other variants affecting the same amino acid (i.e. p.P292T, p.P292L) have been have classified as likely pathogenic in ClinVar and/or have been observed in individuals with Hypophosphatasia (HGMD database), suggesting Pro292 may be important for protein function. The following publication has been ascertained in the context of this evaluation (PMID: 28127875). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as 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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