NM_000478.6(ALPL):c.542C>T (p.Ser181Leu) AND Hypophosphatasia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 25, 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:: RCV002265652.2

Allele description [Variation Report for NM_000478.6(ALPL):c.542C>T (p.Ser181Leu)]

NM_000478.6(ALPL):c.542C>T (p.Ser181Leu)

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.542C>T (p.Ser181Leu)

HGVS:

NC_000001.11:g.21564110C>T
NG_008940.1:g.59746C>T
NM_000478.6:c.542C>TMANE SELECT
NM_001127501.4:c.377C>T
NM_001177520.3:c.311C>T
NM_001369803.2:c.542C>T
NM_001369804.2:c.542C>T
NM_001369805.2:c.542C>T
NP_000469.3:p.Ser181Leu
NP_001120973.2:p.Ser126Leu
NP_001170991.1:p.Ser104Leu
NP_001356732.1:p.Ser181Leu
NP_001356733.1:p.Ser181Leu
NP_001356734.1:p.Ser181Leu
NC_000001.10:g.21890603C>T
NM_000478.4:c.542C>T
NM_000478.5:c.542C>T
P05186:p.Ser181Leu

Protein change:

S104L

Links:

UniProtKB: P05186#VAR_013982; dbSNP: rs199590449

NCBI 1000 Genomes Browser:

rs199590449

Molecular consequence:

NM_000478.6:c.542C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127501.4:c.377C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001177520.3:c.311C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369803.2:c.542C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369804.2:c.542C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369805.2:c.542C>T - 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
SCV002548041	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 25, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11479741, 28436937, 32160374, 33549410 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002548041

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(May 25, 2022)

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

A molecular approach to dominance in hypophosphatasia.

Lia-Baldini AS, Muller F, Taillandier A, Gibrat JF, Mouchard M, Robin B, Simon-Bouy B, Serre JL, Aylsworth AS, Bieth E, Delanote S, Freisinger P, Hu JC, Krohn HP, Nunes ME, Mornet E.

Hum Genet. 2001 Jul;109(1):99-108.

PubMed [citation]

PMID:: 11479741

Efficacy of anti-sclerostin monoclonal antibody BPS804 in adult patients with hypophosphatasia.

Seefried L, Baumann J, Hemsley S, Hofmann C, Kunstmann E, Kiese B, Huang Y, Chivers S, Valentin MA, Borah B, Roubenoff R, Junker U, Jakob F.

J Clin Invest. 2017 Jun 1;127(6):2148-2158. doi: 10.1172/JCI83731. Epub 2017 Apr 24.

PubMed [citation]

PMID:: 28436937
PMCID:: PMC5451251

See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002548041.1

#	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.542C>T (p.Ser181Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three 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-05 in 251130 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ALPL causing Hypophosphatasia (4e-05 vs 0.0035), allowing no conclusion about variant significance. c.542C>T has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with infantile/perinatal-lethal/childhood/odontoid presentations of Hypophosphatasia (example, Seefried_2017, Del Angel_2020). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a partial reduction of normal activity (Del Angel_2020, Lia-Baldini_2001). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was 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

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