NM_000478.6(ALPL):c.571G>A (p.Glu191Lys) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (11 submissions)
Last evaluated:: Jan 31, 2024
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:: RCV000224962.47

Allele description

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000231547	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Apr 13, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12357339, 1409720 Citation Link,
SCV000280679	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 6, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000617526	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 11, 2022)	germline	clinical testing	Citation Link,
SCV000692612	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jan 1, 2024)	germline	clinical testing	Citation Link,
SCV000950872	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12357339, 15671102, 1409720, 20739387, 24569605, 28492532
SCV001743079	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001809281	Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001932789	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001957809	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001965655	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002023091	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 2, 2021)	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	clinical testing
not provided	germline	yes	4	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	7	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Childhood hypophosphatasia due to a de novo missense mutation in the tissue-nonspecific alkaline phosphatase gene.

Taillandier A, Sallinen SL, Brun-Heath I, De Mazancourt P, Serre JL, Mornet E.

J Clin Endocrinol Metab. 2005 Apr;90(4):2436-9. Epub 2005 Jan 25.

PubMed [citation]

PMID:: 15671102

See all PubMed Citations (7)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000231547.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	PubMed (2)

#	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		7	not provided	not provided	not provided

From Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000280679.1

#	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	germline	not provided	not provided	not provided	not provided		not provided	0.000673	not provided	not provided

From GeneDx, SCV000617526.4

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

Description

Published functional studies demonstrate that E191K has delayed membrane anchoring (Brun-Heath et al., 2007) and relatively high residual alkaline phosphatase activity (56% and 88% of wildtype), though no dominant negative effect was observed (Zurutuza et al., 1999; Fauvert et al., 2009; Hofmann et al., 2014); Observed in homozygous state in large population cohorts (gnomAD) and in a clinically unaffected adult relative of an individual referred for genetic testing at GeneDx, supporting that this mild variant leads to disease only when a more severe variant is present on the opposite allele (in trans); 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: 24569605, 20739387, 1409720, 19500388, 11855933, 10332035, 18328985, 17719863, 11438998, 12357339, 29659871, 10679946, 19232125, 27920814, 10737975, 29236161, 15671102, 32160374, 31589614, 33083013, 8606878, 33101980, 34213743, 33093890, 33549410)

#	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

From CeGaT Center for Human Genetics Tuebingen, SCV000692612.25

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	not provided

Description

ALPL: PM3:Very Strong, PM5, PM2:Supporting, PP3, PS3:Supporting

#	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		4	not provided	not provided	not provided

From Invitae, SCV000950872.6

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

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 191 of the ALPL protein (p.Glu191Lys). This variant is present in population databases (rs121918007, gnomAD 1.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with hypophosphatasia (PMID: 12357339, 15671102, 24569605). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Glu174Lys. ClinVar contains an entry for this variant (Variation ID: 13670). 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: 1409720, 20739387, 24569605). 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 Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001743079.3

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

From Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus, SCV001809281.1

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

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001932789.1

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

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001957809.1

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

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001965655.1

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

From Revvity Omics, Revvity, SCV002023091.3

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 9, 2024

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