rs121917724

Positions:

chr19-33387892-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000285.4(PEPD):c.1342G>A(p.Gly448Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000364 in 1,564,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

PEPD
NM_000285.4 missense, splice_region

Scores

Splicing: ADA: 0.8907

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 5.67

Variant links:

Genes affected

PEPD (HGNC:8840): (peptidase D) This gene encodes a member of the peptidase family. The protein forms a homodimer that hydrolyzes dipeptides or tripeptides with C-terminal proline or hydroxyproline residues. The enzyme serves an important role in the recycling of proline, and may be rate limiting for the production of collagen. Mutations in this gene result in prolidase deficiency, which is characterized by the excretion of large amount of di- and tri-peptides containing proline. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

PEPD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 19-33387892-C-T is Pathogenic according to our data. Variant chr19-33387892-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PEPD	NM_000285.4 linkuse as main transcript	c.1342G>A	p.Gly448Arg	missense_variant, splice_region_variant	14/15	ENST00000244137.12
PEPD	NM_001166056.2 linkuse as main transcript	c.1219G>A	p.Gly407Arg	missense_variant, splice_region_variant	12/13
PEPD	NM_001166057.2 linkuse as main transcript	c.1150G>A	p.Gly384Arg	missense_variant, splice_region_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEPD	ENST00000244137.12 linkuse as main transcript	c.1342G>A	p.Gly448Arg	missense_variant, splice_region_variant	14/15	1	NM_000285.4	P1	P12955-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000179

AC:

AN:

167316

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

90520

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000417

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000300

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000361

AC:

AN:

1411860

Hom.:

Cov.:

AF XY:

0.0000444

AC XY:

AN XY:

697646

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000124

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000432

Gnomad4 OTH exome

AF:

0.0000513

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000557

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000171

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Prolidase deficiency

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 25, 2016	The p.Gly448Arg variant in PEPD has been reported in 6 individuals with prolidas e deficiency. Three of these individuals were homozygous and three compound hete rozygous with another pathogenic variant in PEPD (Ledoux 1994, Lupi 2006, Forlin o 2002). This variant has also been identified in 0.027% (2/7412) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs121917724). Although this variant is seen in the general population , its frequency is consistent with a recessive carrier frequency. In addition, i n vitro functional studies provide some evidence that the p.Gly448Arg variant ma y impact protein function (Ledoux 1996, Besio 2013). In summary, this variant me ets our criteria to be classified as pathogenic for prolidase deficiency in an a utosomal recessive manner based upon its co-occurrence in trans with other patho genic variants in patients, low frequency in controls and functional evidence. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	May 14, 2019	This variant has been previously reported as a homozygous or compound heterozygous change in multiple patients with prolidase deficiency (PMID: 8198124, 17142620). Studies using patient fibroblast lines and recombinant prolidase demonstrated that this variant leads to decreased catalytic efficiency, thermal stability and cofactor binding (PMID: 23516557). Additionally, an in vitro experiment in COS-1 cells demonstrated that this variant reduces prolidase activity to undetectable levels (PMID: 8900231). This variant has been classified as Pathogenic by a clinical diagnostic laboratory in the ClinVar database (Variation ID: 213). It is present in the heterozygous state in the gnomAD population database at a frequency of .003% (5/193670) and thus is presumed to be rare. The c.1342G>A (p.Gly448Arg) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1342G>A (p.Gly448Arg) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 11, 2018	The PEPD c.1342G>A (p.Gly448Arg) missense variant has been reported in four studies in which it is found in a total of eight individuals with prolidase deficiency (PD). The variant was found in five individuals in a homozygous state, including a sibling pair, and in three compound heterozygotes, two of whom were related (Ledoux et al. 1994; Forlino et al. 2002; Lupi et al. 2006; Vestita et al. 2017). Ledoux et al. (1994), Lupi et al. (2006) and Besio et al. (2013) demonstrated that prolidase activity in fibroblasts from patients with PD with the p.Gly448Arg variant was reduced to <2% to 13.1% when compared to controls. In addition, transient expression of the p.Gly448Arg variant in COS1 cells produced an inactive enzyme (Ledoux et al. 1996), and a recombinant PEPD enzyme containing the p.Gly448Arg variant showed very low catalytic efficiency, thermal instability, and changes in protein conformations (Besio et al. 2013). Forlino et al. (2002) also showed that cultured PD patient fibroblasts with the p.Gly448Arg variant exhibited multiple cell structure abnormalities. This variant was absent in 150 control chromosomes and is reported at a frequency of 0.000036 in the European (non-Finnish) population. Based on the collective evidence, the p.Gly448Arg variant is classified as pathogenic for prolidase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2002	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Aug 29, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 27, 2021	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 448 of the PEPD protein (p.Gly448Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with prolidase deficiency (PMID: 8198124, 12384772, 17142620, 25460580). ClinVar contains an entry for this variant (Variation ID: 213). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PEPD function (PMID: 8900231, 23516557). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

D;.;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.81

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

5.1

H;.;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-7.5

D;D;D

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

1.0

MutPred

0.99

Gain of MoRF binding (P = 0.0178);.;.;

MVP

0.97

MPC

0.58

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.89

dbscSNV1_RF

Pathogenic

0.74

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over