rs797045185

Positions:

• chr19-33391344-A-C
• chr19-33391344-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000285.4(PEPD):​c.1103T>G​(p.Leu368Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PEPD NM_000285.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 8.66

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 19-33391344-A-C is Pathogenic according to our data. Variant chr19-33391344-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 209998.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEPD	NM_000285.4	c.1103T>G	p.Leu368Arg	missense_variant	13/15	ENST00000244137.12	NP_000276.2
PEPD	NM_001166056.2	c.980T>G	p.Leu327Arg	missense_variant	11/13		NP_001159528.1
PEPD	NM_001166057.2	c.911T>G	p.Leu304Arg	missense_variant	11/13		NP_001159529.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEPD	ENST00000244137.12	c.1103T>G	p.Leu368Arg	missense_variant	13/15	1	NM_000285.4	ENSP00000244137.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459304 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2 AN XY: 725792

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 28, 2023

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 368 of the PEPD protein (p.Leu368Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with prolidase deficiency (PMID: 19308961). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 209998). 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%. 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. -

Prolidase deficiency Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.8	H;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		1.0
MutPred		0.95		Gain of methylation at L368 (P = 0.0019);.;.;
MVP		0.96
MPC		0.64
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99

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

Other links and lift over

dbSNP: rs797045185; hg19: chr19-33882250;