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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001210003	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 12, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 9781036, 10332035, 19232125, 24276437, 25731960, 26432670, 11479741, 19500388, 28492532
SCV001832337	Blueprint Genetics	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	Pathogenic (Nov 30, 2019)	germline	clinical testing	Citation Link,
SCV002817223	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Likely pathogenic (Feb 11, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003817229	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003845631	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 17, 2023)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

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

#	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 Blueprint Genetics, SCV001832337.1

#	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 Athena Diagnostics, SCV002817223.1

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

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

From Revvity Omics, Revvity, SCV003817229.2

#	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

From GeneDx, SCV003845631.1

#	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 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)

#	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

Last Updated: May 19, 2024

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