NM_000478.6(ALPL):c.542C>T (p.Ser181Leu) AND Inborn genetic diseases

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 11, 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:: RCV002516529.2

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]

Observations:

Condition(s)

Name:: Inborn genetic diseases
Identifiers:: MeSH: D030342; MedGen: C0950123

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003596483	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Likely pathogenic (Jan 11, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 33977024, 33549410, 17253930, 11479741, 32160374 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003596483

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Likely pathogenic
(Jan 11, 2022)

germline

clinical testing

PubMed (5)
[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	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Excellent response to asfotase alfa treatment in an adolescent patient with hypophosphatasia.

Strandbech OS, Lund A, Ostergaard E.

JIMD Rep. 2021 May;59(1):10-15. doi: 10.1002/jmd2.12198.

PubMed [citation]

PMID:: 33977024
PMCID:: PMC8100395

Utility of genetic testing for prenatal presentations of hypophosphatasia.

Sperelakis-Beedham B, Taillandier A, Domingues C, Guberto M, Colin E, Porquet-Bordes V, Rothenbuhler A, Salles JP, Wenkert D, Zankl A, Muti C, Bacrot S, Simon-Bouy B, Mornet E.

Mol Genet Metab. 2021 Mar;132(3):198-203. doi: 10.1016/j.ymgme.2021.01.009. Epub 2021 Jan 27.

PubMed [citation]

PMID:: 33549410

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV003596483.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (5)

Description

The c.542C>T (p.S181L) alteration is located in exon 6 (coding exon 5) of the ALPL gene. This alteration results from a C to T substitution at nucleotide position 542, causing the serine (S) at amino acid position 181 to be replaced by a leucine (L). Based on the available evidence, this alteration is classified as likely pathogenic for autosomal recessive hypophosphatasia; however, it is unlikely to be causative of autosomal dominant hypophosphatasia. Based on data from gnomAD, the T allele has an overall frequency of <0.01% (10/251130) total alleles studied. The highest observed frequency was 0.04% (4/10066) of Ashkenazi Jewish alleles. This alteration was detected in trans with a pathogenic ALPL mutation in a fetus with severe prenatal hypophosphatasia (Sperelakis-Beedham, 2021), as well as in the homozygous state in an individual with hypophosphatasia that presented in the neonatal period (Strandbech, 2021). In addition, this alteration was detected along with a second ALPL variant in an individual with subnormal serum alkaline phosphatase and disproportional dwarfism (Spentchian, 2006; Lia-Baldini, 2001), as well as in several other individuals with hypophosphatasia (del Angel, 2020). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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