NM_000285.4(PEPD):c.826G>A (p.Asp276Asn) AND not provided

Germline classification:: Pathogenic (2 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:: RCV000520088.7

Allele description [Variation Report for NM_000285.4(PEPD):c.826G>A (p.Asp276Asn)]

NM_000285.4(PEPD):c.826G>A (p.Asp276Asn)

Gene:

PEPD:peptidase D [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.11

Genomic location:

Preferred name:

NM_000285.4(PEPD):c.826G>A (p.Asp276Asn)

HGVS:

NC_000019.10:g.33401862C>T
NG_013358.2:g.125032G>A
NM_000285.4:c.826G>AMANE SELECT
NM_001166056.2:c.703G>A
NM_001166057.2:c.634G>A
NP_000276.2:p.Asp276Asn
NP_001159528.1:p.Asp235Asn
NP_001159529.1:p.Asp212Asn
NC_000019.9:g.33892768C>T
NG_013358.1:g.125032G>A
NM_000285.3:c.826G>A
P12955:p.Asp276Asn

Protein change:

D212N; ASP276ASN

Links:

UniProtKB: P12955#VAR_004404; OMIM: 613230.0001; dbSNP: rs121917721

NCBI 1000 Genomes Browser:

rs121917721

Molecular consequence:

NM_000285.4:c.826G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001166056.2:c.703G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001166057.2:c.634G>A - 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
SCV000617626	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 24, 2023)	germline	clinical testing	Citation Link,
SCV003497076	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 12, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17142620, 2365824, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000617626

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Aug 24, 2023)

germline

clinical testing

Citation Link,

SCV003497076

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 12, 2024)

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	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

Citations

PubMed

Molecular characterisation of six patients with prolidase deficiency: identification of the first small duplication in the prolidase gene and of a mutation generating symptomatic and asymptomatic outcomes within the same family.

Lupi A, Rossi A, Campari E, Pecora F, Lund AM, Elcioglu NH, Gultepe M, Di Rocco M, Cetta G, Forlino A.

J Med Genet. 2006 Dec;43(12):e58.

PubMed [citation]

PMID:: 17142620
PMCID:: PMC2563206

A single nucleotide change in the prolidase gene in fibroblasts from two patients with polypeptide positive prolidase deficiency. Expression of the mutant enzyme in NIH 3T3 cells.

Tanoue A, Endo F, Kitano A, Matsuda I.

J Clin Invest. 1990 Jul;86(1):351-5.

PubMed [citation]

PMID:: 2365824
PMCID:: PMC296729

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000617626.5

#	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 demonstrate a damaging effect: severe impaired catalytic activity (Tanoue et al., 1990); This variant is associated with the following publications: (PMID: 31107408, 18340504, 29930383, 30066404, 15309682, 10721675, 17142620, 31588604, 2365824, 33726816)

#	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 Invitae, SCV003497076.2

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 276 of the PEPD protein (p.Asp276Asn). This variant is present in population databases (rs121917721, gnomAD 0.01%). This missense change has been observed in individual(s) with prolidase deficiency (PMID: 2365824, 17142620). ClinVar contains an entry for this variant (Variation ID: 208). 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 PEPD protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PEPD function (PMID: 2365824). 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

Last Updated: Feb 20, 2024

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