NM_000860.6(HPGD):c.418G>C (p.Ala140Pro) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 10, 2022
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:: RCV001781205.5

Allele description [Variation Report for NM_000860.6(HPGD):c.418G>C (p.Ala140Pro)]

NM_000860.6(HPGD):c.418G>C (p.Ala140Pro)

Gene:

HPGD:15-hydroxyprostaglandin dehydrogenase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q34.1

Genomic location:

Preferred name:

NM_000860.6(HPGD):c.418G>C (p.Ala140Pro)

HGVS:

NC_000004.12:g.174508699C>G
NG_011689.1:g.18943G>C
NM_000860.6:c.418G>CMANE SELECT
NM_001145816.3:c.418G>C
NM_001256301.1:c.55G>C
NM_001256305.2:c.418G>C
NM_001256306.2:c.218-13075G>C
NM_001256307.2:c.55G>C
NM_001363574.2:c.418G>C
NP_000851.2:p.Ala140Pro
NP_001139288.1:p.Ala140Pro
NP_001243230.1:p.Ala19Pro
NP_001243234.1:p.Ala140Pro
NP_001243236.1:p.Ala19Pro
NP_001350503.1:p.Ala140Pro
NC_000004.11:g.175429850C>G
P15428:p.Ala140Pro

Protein change:

A140P; ALA140PRO

Links:

UniProtKB: P15428#VAR_046209; OMIM: 601688.0001; dbSNP: rs121434480

NCBI 1000 Genomes Browser:

rs121434480

Molecular consequence:

NM_001256306.2:c.218-13075G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000860.6:c.418G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001145816.3:c.418G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001256301.1:c.55G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001256305.2:c.418G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001256307.2:c.55G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001363574.2:c.418G>C - 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
SCV003525617	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 10, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18500342, 32282352, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003525617

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 10, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy.

Uppal S, Diggle CP, Carr IM, Fishwick CW, Ahmed M, Ibrahim GH, Helliwell PS, Latos-Bieleńska A, Phillips SE, Markham AF, Bennett CP, Bonthron DT.

Nat Genet. 2008 Jun;40(6):789-93. doi: 10.1038/ng.153. Epub 2008 May 25. Erratum in: Nat Genet. 2008 Jul;40(7):927.

PubMed [citation]

PMID:: 18500342

Digital clubbing as the predominant manifestation of hypertrophic osteoarthropathy caused by pathogenic variants in HPGD in three Indian families.

Radhakrishnan P, Jacob P, Nayak SS, Gowrishankar K, Prakash Soni J, Shukla A, Girisha KM.

Clin Dysmorphol. 2020 Jul;29(3):123-126. doi: 10.1097/MCD.0000000000000324.

PubMed [citation]

PMID:: 32282352

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003525617.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HPGD function (PMID: 18500342). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 7917). This missense change has been observed in individuals with clinical features of hypertrophic osteoarthropathy (PMID: 18500342, 32282352). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121434480, gnomAD 0.06%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 140 of the HPGD protein (p.Ala140Pro).

#	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: Sep 29, 2024

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