NM_000478.6(ALPL):c.571G>A (p.Glu191Lys) AND Infantile hypophosphatasia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 12, 2019
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:: RCV000014658.40

Allele description [Variation Report for NM_000478.6(ALPL):c.571G>A (p.Glu191Lys)]

NM_000478.6(ALPL):c.571G>A (p.Glu191Lys)

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.571G>A (p.Glu191Lys)

Other names:

E174K

HGVS:

NC_000001.11:g.21564139G>A
NG_008940.1:g.59775G>A
NM_000478.6:c.571G>AMANE SELECT
NM_001127501.4:c.406G>A
NM_001177520.3:c.340G>A
NM_001369803.2:c.571G>A
NM_001369804.2:c.571G>A
NM_001369805.2:c.571G>A
NP_000469.3:p.Glu191Lys
NP_000469.3:p.Glu191Lys
NP_001120973.2:p.Glu136Lys
NP_001170991.1:p.Glu114Lys
NP_001356732.1:p.Glu191Lys
NP_001356733.1:p.Glu191Lys
NP_001356734.1:p.Glu191Lys
NC_000001.10:g.21890632G>A
NM_000478.3:c.571G>A
NM_000478.4:c.571G>A
NM_000478.5:c.571G>A
P05186:p.Glu191Lys

Protein change:

E114K; GLU174LYS

Links:

UniProtKB: P05186#VAR_006158; OMIM: 171760.0008; dbSNP: rs121918007

NCBI 1000 Genomes Browser:

rs121918007

Molecular consequence:

NM_000478.6:c.571G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127501.4:c.406G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001177520.3:c.340G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369803.2:c.571G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369804.2:c.571G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369805.2:c.571G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Infantile hypophosphatasia
Identifiers:: MedGen: C0268412; Orphanet: 436; OMIM: 241500

Recent activity

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Saccharibacillus brassicae ATSA2
Saccharibacillus brassicae ATSA2

biosample
txid2583377[Organism:exp] AND "type material"[Attribute Name] (1)
BioSample
Homo sapiens TBC1 domain family member 32 (TBC1D32), RefSeqGene on chromosome 6
Homo sapiens TBC1 domain family member 32 (TBC1D32), RefSeqGene on chromosome 6
gi|665821334|ref|NG_034203.1|

Nucleotide
SRP033127 (503)
SRA
glutamate carboxypeptidase 2 isoform X6 [Homo sapiens]
glutamate carboxypeptidase 2 isoform X6 [Homo sapiens]
gi|1034572748|ref|XP_011518260.2|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000034913	OMIM	no assertion criteria provided	Pathogenic (Oct 1, 2002)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 1409720, 12357339
SCV001193949	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Nov 12, 2019)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 25731960, 11438998, 19232125, 10679946, 11855933, 10332035 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000034913

OMIM

no assertion criteria provided

Pathogenic
(Oct 1, 2002)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV001193949

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))

Pathogenic
(Nov 12, 2019)

unknown

clinical testing

PubMed (6)
[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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia.

Henthorn PS, Raducha M, Fedde KN, Lafferty MA, Whyte MP.

Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9924-8.

PubMed [citation]

PMID:: 1409720
PMCID:: PMC50246

Evidence of a founder effect for the tissue-nonspecific alkaline phosphatase (TNSALP) gene E174K mutation in hypophosphatasia patients.

Hérasse M, Spentchian M, Taillandier A, Mornet E.

Eur J Hum Genet. 2002 Oct;10(10):666-8.

PubMed [citation]

PMID:: 12357339

See all PubMed Citations (8)

Details of each submission

From OMIM, SCV000034913.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In fibroblasts from a girl who presented at 2 months of age with severe hypophosphatasia (241500) and died at age 8 months, Henthorn et al. (1992) identified compound heterozygosity for 2 mutations in the ALPL gene: a 747G-A transition in exon 6, resulting in a glu174-to-lys (E174K) substitution, and a 1309A-T transversion in exon 10, resulting in an asp361-to-val (D361V) substitution (171760.0009).

For discussion of the asp378-to-val (D378V) mutation found in compound heterozygous state in the ALPL gene in patients with childhood (241510) or adult (146300) hypophosphatasia by Henthorn et al. (1992), see 171760.0003.

Herasse et al. (2002) investigated whether the E174K mutation had a unique origin or multiple origins arising from de novo mutations by genotyping 3 intragenic polymorphisms in patients with E174K and unaffected related individuals. Because all of the E174K mutations were found on a common ancestral haplotype, the authors suggested that a founder mutation occurred on a single chromosome in northwestern Europe and spread by human migration.

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

From Myriad Genetics, Inc., SCV001193949.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

NM_000478.4(ALPL):c.571G>A(E191K, aka E174K) is classified as pathogenic in the context of hypophosphatasia. Sources cited for classification include the following: PMID 25731960, 11438998, 19232125, 10679946, 11855933 and 10332035. Classification of NM_000478.4(ALPL):c.571G>A(E191K, aka E174K) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

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

Last Updated: May 12, 2024

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