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NM_000478.6(ALPL):c.550C>T (p.Arg184Trp) AND not provided

Germline classification:
Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:
Jan 12, 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:
RCV001046115.12

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)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001210003Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 12, 2024)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV001832337Blueprint Genetics
criteria provided, single submitter

(Blueprint Genetics Variant Classification Scheme)
Pathogenic
(Nov 30, 2019)
germlineclinical testing

Citation Link,

SCV002817223Athena Diagnostics
criteria provided, single submitter

(Athena Diagnostics Criteria)
Likely pathogenic
(Feb 11, 2021)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003817229Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Aug 3, 2022)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003845631GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)
Pathogenic
(Mar 17, 2023)
germlineclinical testing

Citation Link

Summary from all submissions

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

Correlations of genotype and phenotype in hypophosphatasia.

Zurutuza L, Muller F, Gibrat JF, Taillandier A, Simon-Bouy B, Serre JL, Mornet E.

Hum Mol Genet. 1999 Jun;8(6):1039-46.

PubMed [citation]
PMID:
10332035
See all PubMed Citations (11)

Details of each submission

From Invitae, SCV001210003.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 184 of the ALPL protein (p.Arg184Trp). This variant is present in population databases (rs763159520, gnomAD 0.003%). This missense change has been observed in individual(s) with hypophosphatasia and thus appears to be associated with both dominant and recessive ALPL-related disease (PMID: 9781036, 10332035, 11479741, 19232125, 19500388, 24276437, 25731960, 26432670). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg167Trp. ClinVar contains an entry for this variant (Variation ID: 521379). 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: 11479741, 19500388). For these reasons, this variant has been classified as Pathogenic.

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

From Blueprint Genetics, SCV001832337.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Athena Diagnostics, SCV002817223.1

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

Description

This variant has been identified in multiple individuals associated with autosomal dominant and recessive ALPL-related disorders (PMID: 25731960, 32160374, 31600233, 19232125, 19500388). Assessment of experimental evidence suggests this variant may have a dominant-negative effect and could result in abnormal protein function (PMID: 19500388, 31707452). The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.

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

From Revvity Omics, Revvity, SCV003817229.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From GeneDx, SCV003845631.1

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

Description

Published functional studies show significantly reduced activity compared to wildtype and demonstrate a dominant-negative effect (Fauvert et al., 2009; Del Angel et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25731960, 23791648, 26432670, 19232125, 26219717, 9781036, 19500388, 11479741, 31600233, 29236161, 31707452, 35068125, 33349304, 36553293, 33814268, 36097602, 30049651, 24276437, 10332035, 32160374, 33549410)

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

Last Updated: Jun 17, 2024