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NM_000478.6(ALPL):c.550C>T (p.Arg184Trp) AND Inborn genetic diseases

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 15, 2024
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:
RCV000623730.4

Allele description [Variation Report for NM_000478.6(ALPL):c.550C>T (p.Arg184Trp)]

NM_000478.6(ALPL):c.550C>T (p.Arg184Trp)

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.550C>T (p.Arg184Trp)
Other names:
p.Arg184Trp
HGVS:
  • NC_000001.11:g.21564118C>T
  • NG_008940.1:g.59754C>T
  • NM_000478.6:c.550C>TMANE SELECT
  • NM_001127501.4:c.385C>T
  • NM_001177520.3:c.319C>T
  • NM_001369803.2:c.550C>T
  • NM_001369804.2:c.550C>T
  • NM_001369805.2:c.550C>T
  • NP_000469.3:p.Arg184Trp
  • NP_001120973.2:p.Arg129Trp
  • NP_001170991.1:p.Arg107Trp
  • NP_001356732.1:p.Arg184Trp
  • NP_001356733.1:p.Arg184Trp
  • NP_001356734.1:p.Arg184Trp
  • NC_000001.10:g.21890611C>T
  • NM_000478.4:c.550C>T
  • NM_000478.5:c.550C>T
Protein change:
R107W
Links:
dbSNP: rs763159520
NCBI 1000 Genomes Browser:
rs763159520
Molecular consequence:
  • NM_000478.6:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127501.4:c.385C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001177520.3:c.319C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369803.2:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369804.2:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369805.2:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Inborn genetic diseases
Identifiers:
MeSH: D030342; MedGen: C0950123

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000741935Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Pathogenic
(Apr 15, 2024)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

Identification of fifteen novel mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in European patients with severe hypophosphatasia.

Mornet E, Taillandier A, Peyramaure S, Kaper F, Muller F, Brenner R, Bussière P, Freisinger P, Godard J, Le Merrer M, Oury JF, Plauchu H, Puddu R, Rival JM, Superti-Furga A, Touraine RL, Serre JL, Simon-Bouy B.

Eur J Hum Genet. 1998 Jul-Aug;6(4):308-14.

PubMed [citation]
PMID:
9781036

Orodental phenotype and genotype findings in all subtypes of hypophosphatasia.

Reibel A, Manière MC, Clauss F, Droz D, Alembik Y, Mornet E, Bloch-Zupan A.

Orphanet J Rare Dis. 2009 Feb 21;4:6. doi: 10.1186/1750-1172-4-6.

PubMed [citation]
PMID:
19232125
PMCID:
PMC2654544
See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV000741935.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

The c.550C>T (p.R184W) alteration is located in exon 6 (coding exon 5) of the ALPL gene. This alteration results from a C to T substitution at nucleotide position 550, causing the arginine (R) at amino acid position 184 to be replaced by a tryptophan (W). This variant has been identified in conjunction with other ALPLvariant(s) in individuals with features consistent with ALPL-related hypophosphatasia (Mornet, 1993; Reibel, 2009; Rockman-Greenberg, 2022; Yazici, 2022). In multiple assays testing ALPL function, this variant showed a significant decrease in alkaline phosphatase activity; however, in assays testing a dominant negative effect, this variant showed varying results (Lia-Baldini, 2001; Fauvert, 2009; Michigami, 2020; Del Angel, 2020). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (4/282484) total alleles studied. The highest observed frequency was 0.003% (1/35408) of Latino alleles. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of the ALPL c.550C>T (p.R184W) alteration is pathogenic for autosomal dominant and autosomal recessive ALPL-related hypophosphatasia (loss of function mechanism of disease); however, its clinical significance for autosomal dominant ALPL-related hypophosphatasia (dominant negative mechanism of disease) is uncertain.

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

Last Updated: Jun 17, 2024