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

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jun 13, 2022
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:: RCV000014659.41

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]

Observations:

Condition(s)

Name:: Childhood hypophosphatasia
Identifiers:: MedGen: C0220743; Orphanet: 436; OMIM: 241510

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000034914	OMIM	no assertion criteria provided	Pathogenic (Oct 1, 2002)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 1409720, 12357339
SCV000536856	Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq	no assertion criteria provided	Likely pathogenic (Oct 27, 2015)	germline	research	PubMed (5) [See all records that cite these PMIDs] 1409720, 17719863, 19500388, 24569605, 20739387
SCV001439987	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002104243	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 18, 2021)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12357339, 24569605, 25741868
SCV002580909	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 13, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	research

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

Delayed transport of tissue-nonspecific alkaline phosphatase with missense mutations causing hypophosphatasia.

Brun-Heath I, Lia-Baldini AS, Maillard S, Taillandier A, Utsch B, Nunes ME, Serre JL, Mornet E.

Eur J Med Genet. 2007 Sep-Oct;50(5):367-78. Epub 2007 Jul 21.

PubMed [citation]

PMID:: 17719863

See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000034914.2

#	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 Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq, SCV000536856.1

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

#	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 Institute of Human Genetics, University of Leipzig Medical Center, SCV001439987.1

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

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

From Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital, SCV002104243.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The c.571G>A (p.Glu191Lys) variant in the ALPL gene is observed at a minor allele frequency (MAF) of 1.6% in the European (Finnish) population, including 3 homozygous individuals (https://gnomad.broadinstitute.org/variant/1-21890632-G-A). This variant has been reported in multiple individuals affected with autosomal recessive hypophosphatasia and observed to segregate with the disease in family studies (PMID: 12357339, PMID: 24569605). In vitro functional studies have suggested this variant mildly reduced the alkaline phosphatase (ALP) activity (PMID: 24569605).

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

From MGZ Medical Genetics Center, SCV002580909.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (1)

#	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		3	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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