NM_000285.4:c.1342G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 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

Publications

15 publications found

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 Gene-Disease associations (from GenCC):

prolidase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

PEPD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEPD	NM_000285.4 link	c.1342G>A	p.Gly448Arg	missense_variant, splice_region_variant	Exon 14 of 15	ENST00000244137.12	NP_000276.2	P12955-1A0A140VJR2
PEPD	NM_001166056.2 link	c.1219G>A	p.Gly407Arg	missense_variant, splice_region_variant	Exon 12 of 13		NP_001159528.1	P12955-2
PEPD	NM_001166057.2 link	c.1150G>A	p.Gly384Arg	missense_variant, splice_region_variant	Exon 12 of 13		NP_001159529.1	P12955-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEPD	ENST00000244137.12 link	c.1342G>A	p.Gly448Arg	missense_variant, splice_region_variant	Exon 14 of 15	1	NM_000285.4	ENSP00000244137.5		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

GnomAD2 exomes

AF:

0.0000179

AC:

AN:

167316

AF XY:

0.0000221

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 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

African (AFR)

AF:

0.00

AC:

AN:

32370

American (AMR)

AF:

0.00

AC:

AN:

37418

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25284

East Asian (EAS)

AF:

0.00

AC:

AN:

37206

South Asian (SAS)

AF:

0.0000124

AC:

AN:

80396

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48754

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5056

European-Non Finnish (NFE)

AF:

0.0000432

AC:

AN:

1086888

Other (OTH)

AF:

0.0000513

AC:

AN:

58488

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41584

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Oct 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Dec 11, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

May 14, 2019

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Oct 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 29, 2017

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Mar 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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;.;.

PhyloP100

5.7

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

Mutation Taster

=14/86

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over