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NM_000478.6(ALPL):c.571G>A (p.Glu191Lys) AND ALPL-related disorder

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Aug 23, 2024
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV004739305.1

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:
ALPL-related disorder
Synonyms:
ALPL-related disorders; ALPL-related condition
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005344780PreventionGenetics, part of Exact Sciences
no assertion criteria provided
Pathogenic
(Aug 23, 2024) 		germlineclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV005344780.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The ALPL c.571G>A variant is predicted to result in the amino acid substitution p.Glu191Lys. This variant, alternatively referred to as p.Glu174Lys using legacy nomenclature, has been reported in the compound heterozygous state in numerous individuals with hypophosphatasia (HPP), predominantly childhood, adult and odontohypophosphatasia forms (see, for example, Henthorn et al. 1992. PubMed ID: 1409720, reported as 747A (p.Glu174Lys); Fauvert et al. 2009. PubMed ID: 19500388; Hofmann et al. 2014. PubMed ID: 24569605). It has also been reported in the heterozygous state in individuals with odontohypophosphatasia (Fauvert et al. 2009. PubMed ID: 19500388). This variant was also shown to segregate with HPP in two families (Henthorn et al. 1992. PubMed ID: 1409720; Hofmann et al. 2014. PubMed ID: 24569605). Functional studies using COS7 and HEK293 cells show mild reduction in tissue non-specific alkaline phosphatase (TNSALP) activity and also indicate this variant does not result in a dominant-negative effect. It is speculated that phenotypic variability is related to either an unidentified second variant or varying alkaline phosphatase tolerance thresholds (Fauvert et al. 2009. PubMed ID: 19500388; Hofmann et al. 2014. PubMed ID: 24569605). An alternate nucleotide change affecting the same amino acid, p.Glu191Gly (p.Glu174Gly using legacy nomenclature), has been reported in a patient with HPP (Goseki-Sone et al. 1998. PubMed ID: 9452105, reported as p.Glu174Gly; Michigami et al. 2019. PubMed ID: 31707452). This variant is reported in 1.7% of alleles in individuals of European (Finnish) descent in gnomAD, including 5 homozygotes. Reduced penetrance and expressivity is known in ALPL-related disease. This variant is interpreted as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 26, 2024