rs794728007

Positions:

chr19-33413620-GAGT-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong

The NM_000285.4(PEPD):c.692_694delACT(p.Tyr231del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,589,208 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

PEPD
NM_000285.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 3.28

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:

PEPD (HGNC:):

PEPD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000285.4. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 19-33413620-GAGT-G is Pathogenic according to our data. Variant chr19-33413620-GAGT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 328810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEPD	NM_000285.4 linkuse as main transcript	c.692_694delACT	p.Tyr231del	disruptive_inframe_deletion	10/15	ENST00000244137.12	NP_000276.2	P12955-1A0A140VJR2
PEPD	NM_001166056.2 linkuse as main transcript	c.569_571delACT	p.Tyr190del	disruptive_inframe_deletion	8/13		NP_001159528.1	P12955-2
PEPD	NM_001166057.2 linkuse as main transcript	c.500_502delACT	p.Tyr167del	disruptive_inframe_deletion	8/13		NP_001159529.1	P12955-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEPD	ENST00000244137.12 linkuse as main transcript	c.692_694delACT	p.Tyr231del	disruptive_inframe_deletion	10/15	1	NM_000285.4	ENSP00000244137.5		P12955-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

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:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000163

AC:

AN:

208060

Hom.:

AF XY:

0.000151

AC XY:

AN XY:

112546

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000355

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000241

Gnomad OTH exome

AF:

0.000190

GnomAD4 exome

AF:

0.000188

AC:

270

AN:

1436872

Hom.:

AF XY:

0.000166

AC XY:

118

AN XY:

712412

show subpopulations

Gnomad4 AFR exome

AF:

0.0000605

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000218

Gnomad4 OTH exome

AF:

0.000236

GnomAD4 genome

AF:

0.000138

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.000159

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Prolidase deficiency

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Apr 20, 2021	ACMG classification criteria: PS3 supporting, PS4 supporting, PM2, PM3, PM4 -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Dec 18, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The PEPD c.692_694delACT (p.Tyr231del) variant is reported in one study in which it is found in two unrelated Portuguese individuals with prolidase deficiency in a homozygous state (Lupi et al. 2004). Control data are unavailable for this variant which is reported at a frequency of 0.00044 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in cultured fibroblasts from these two individuals showed significantly decreased prolidase enzyme expression and activity compared to control fibroblasts (Lupi et al. 2004; Besio et al. 2013). Besio et al. (2013) demonstrated the variant resulted in reduced thermal stability, low catalytic efficiency and impaired Mn(II) cofactor binding of PEPD. Based on the evidence, the p.Tyr231del variant is classified as likely 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	Jan 01, 2004	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 29, 2024	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This variant, c.692_694del, results in the deletion of 1 amino acid(s) of the PEPD protein (p.Tyr231del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs745834191, gnomAD 0.03%). This variant has been observed in individual(s) with prolidase deficiency (PMID: 15309682, 33877262). ClinVar contains an entry for this variant (Variation ID: 328810). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects PEPD function (PMID: 23516557). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2023	Published functional studies demonstrate that this variant significantly reduces enzyme activity compared to wildtype (Lupi et al., 2004; Besio et al., 2013); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23516557, 33877262, 15309682) -

PEPD-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 08, 2024

The PEPD c.692_694delACT variant is predicted to result in an in-frame deletion (p.Tyr231del). This variant has been reported in the homozygous state in patients with prolidase deficiency (described as Y231del in Lupi et al. 2004. PubMed ID: 15309682). This variant has also been reported in the compound heterozygous state in another patient with prolidase deficiency, however this patient also had a second PEPD variant present in cis with the c.692_694delACT (p.Tyr231del) variant (Linhares et al. 2021. PubMed ID: 33877262). Prolidase activity was significantly reduced in patient fibroblasts carrying the homozygous p.Tyr231del variant, and recombinant p.Tyr231del protein showed loss of catalytic efficiency, thermal instability, and changes in protein confirmation (described as 231delY in Besio et al. 2013. PubMed ID: 23516557). This variant is reported in 0.035% of alleles in individuals of Latino descent in gnomAD. Taken together, we interpret as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

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