NM_000478.6(ALPL):c.542C>T (p.Ser181Leu) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Dec 22, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000729215.13

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000856857	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely pathogenic (Sep 12, 2017)	germline	clinical testing	Citation Link,
SCV001210953	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 22, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16583935, 17253930, 32160374, 11479741, 28492532
SCV001814029	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Sep 20, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000856857

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Likely pathogenic
(Sep 12, 2017)

germline

clinical testing

Citation Link,

SCV001210953

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 22, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001814029

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Sep 20, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

[Hypophosphatasia: report of two affected girls with spontaneous improvement of skeletal defects].

Ligutić I, Barisić I, Anticević D, Vrdoljak J.

Lijec Vjesn. 2005 Nov-Dec;127(11-12):288-92. Croatian.

PubMed [citation]

PMID:: 16583935

Characterization of missense mutations and large deletions in the ALPL gene by sequencing and quantitative multiplex PCR of short fragments.

Spentchian M, Brun-Heath I, Taillandier A, Fauvert D, Serre JL, Simon-Bouy B, Carvalho F, Grochova I, Mehta SG, Müller G, Oberstein SL, Ogur G, Sharif S, Mornet E.

Genet Test. 2006 Winter;10(4):252-7.

PubMed [citation]

PMID:: 17253930

See all PubMed Citations (5)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000856857.1

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

#	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		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001210953.5

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

Description

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 181 of the ALPL protein (p.Ser181Leu). This variant is present in population databases (rs199590449, gnomAD 0.04%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 11479741, 16583935, 17253930, 32160374). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as S164L. ClinVar contains an entry for this variant (Variation ID: 188798). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ALPL function (PMID: 11479741). For these reasons, this variant has been 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

From GeneDx, SCV001814029.2

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

Description

Observed as heterozygous with and without another ALPL variant in patients with hypophosphatasia in published literature (Spentchian et al., 2006; Nielson et al., 2012; Tenorio et al., 2017; Del Angel et al., 2020; Jandl et al., 2021); Published functional studies demonstrate a damaging effect on enzyme activity (Lia-Baldini et al., 2001); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21956185, 11479741, 28127875, 26783040, 17253930, 16583935, 32160374, 33191482, 33549410, 33601892, 31589614, 33977024, 37600704, 36444396)

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

Last Updated: Sep 29, 2024

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