chr22-18918421-A-G

Position:

chr22-18918421-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PS1_ModeratePP5BP4BS2

The ENST00000357068.11(PRODH):c.1322T>C(p.Leu441Pro) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L441Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., cov: 3)

Exomes 𝑓: 0.0039 ( 50 hom. )

Consequence

PRODH
ENST00000357068.11 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:7O:1

Conservation

PhyloP100: 6.87

Variant links:

Genes affected

PRODH (HGNC:9453): (proline dehydrogenase 1) This gene encodes a mitochondrial protein that catalyzes the first step in proline degradation. Mutations in this gene are associated with hyperprolinemia type 1 and susceptibility to schizophrenia 4 (SCZD4). This gene is located on chromosome 22q11.21, a region which has also been associated with the contiguous gene deletion syndromes, DiGeorge and CATCH22. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2010]

PRODH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PS1

Transcript ENST00000357068.11 (PRODH) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PP5

Variant 22-18918421-A-G is Pathogenic according to our data. Variant chr22-18918421-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 4008.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Pathogenic=2, Uncertain_significance=6}. Variant chr22-18918421-A-G is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.06687951). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 50 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PRODH	NM_016335.6 linkuse as main transcript	c.1322T>C	p.Leu441Pro	missense_variant	11/14	ENST00000357068.11	NP_057419.5
PRODH	NM_001195226.2 linkuse as main transcript	c.998T>C	p.Leu333Pro	missense_variant	11/14		NP_001182155.2
PRODH	NM_001368250.2 linkuse as main transcript	c.998T>C	p.Leu333Pro	missense_variant	11/14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11 linkuse as main transcript	c.1322T>C	p.Leu441Pro	missense_variant	11/14	1	NM_016335.6	ENSP00000349577	P3

Frequencies

GnomAD3 genomes

AF:

0.00253

AC:

AN:

11466

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00278

Gnomad AMI

AF:

0.0476

Gnomad AMR

AF:

0.00333

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00440

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00146

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00191

Gnomad OTH

AF:

0.00521

GnomAD3 exomes

AF:

0.00521

AC:

1303

AN:

249888

Hom.:

AF XY:

0.00507

AC XY:

686

AN XY:

135246

show subpopulations

Gnomad AFR exome

AF:

0.00472

Gnomad AMR exome

AF:

0.00661

Gnomad ASJ exome

AF:

0.00550

Gnomad EAS exome

AF:

0.00597

Gnomad SAS exome

AF:

0.00446

Gnomad FIN exome

AF:

0.00436

Gnomad NFE exome

AF:

0.00496

Gnomad OTH exome

AF:

0.00737

GnomAD4 exome

AF:

0.00392

AC:

748

AN:

190684

Hom.:

Cov.:

AF XY:

0.00387

AC XY:

388

AN XY:

100218

show subpopulations

Gnomad4 AFR exome

AF:

0.00403

Gnomad4 AMR exome

AF:

0.00546

Gnomad4 ASJ exome

AF:

0.00418

Gnomad4 EAS exome

AF:

0.00440

Gnomad4 SAS exome

AF:

0.00335

Gnomad4 FIN exome

AF:

0.00283

Gnomad4 NFE exome

AF:

0.00380

Gnomad4 OTH exome

AF:

0.00395

GnomAD4 genome

AF:

0.00253

AC:

AN:

11484

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

AN XY:

5078

show subpopulations

Gnomad4 AFR

AF:

0.00276

Gnomad4 AMR

AF:

0.00333

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00446

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00146

Gnomad4 NFE

AF:

0.00191

Gnomad4 OTH

AF:

0.00495

Alfa

AF:

0.00478

Hom.:

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.00674

AC:

ExAC

AF:

0.00575

AC:

698

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:7Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Proline dehydrogenase deficiency

Pathogenic:2Uncertain:5

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2022	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 441 of the PRODH protein (p.Leu441Pro). This variant is present in population databases (rs2904551, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This variant has been reported in individuals affected with type I hyperprolinemia and has been reported to be associated with neurological manifestations when present in the homozygous state. It is also reported to present at a higher frequency in affected individuals than unaffected controls in a small cohort from the French population (PMID: 12217952, 20524212). ClinVar contains an entry for this variant (Variation ID: 4008). 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 PRODH protein function. Experimental studies have shown that this missense change affects PRODH function (PMID: 15662599). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 29, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	In silico prediction tools and conservation analysis predicted that this variant was probably damaging to the protein structure/function (REVEL: 0.732>=0.6, 3CNET: 0.975>=0.75). A missense variant is a common mechanism associated with Hyperprolinemia, type I. Amino acid change identical to known pathogenic variant has been previously reported with established evidence (ClinVar ID: VCV000004008, PMID:12217952). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 29, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2005	- -

not provided

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 19, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	PRODH: PM3, PM2:Supporting, PP3, PP4, PS3:Supporting -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PRODH p.Leu441Pro variant was identified in 4 of 934 proband chromosomes (frequency: 0.0043) from individuals or families with schizophrenia (Jacquet_2002_PMID:12217952; Jacquet_2005_PMID:1549470). This variant was also identified as a homozygous variant in two unrelated children with severe type I hyperprolinemia with neurological manifestations (Jacquet_2002_PMID:12217952). In transient transfection assays, this variant was found to severely (>70%) reduce POX activity (Bender_2005_PMID:15662599). The variant was identified in dbSNP (ID: rs2904551), LOVD 3.0 (classified as a VUS and pathogenic) and ClinVar (classified as likely pathogenic by GeneDx, Center for Pediatric Genomic Medicine Children's Mercy Hospital and Clinics and CeGaT Praxis fuer Humangenetik Tuebingen, and as uncertain significance by Invitae for Proline dehydrogenase deficiency). The variant was identified in control databases in 1454 of 281208 chromosomes (13 homozygous) at a frequency of 0.005171 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 231 of 35338 chromosomes (freq: 0.006537), Other in 46 of 7194 chromosomes (freq: 0.006394), East Asian in 117 of 19810 chromosomes (freq: 0.005906), Ashkenazi Jewish in 57 of 10298 chromosomes (freq: 0.005535), European (non-Finnish) in 639 of 128296 chromosomes (freq: 0.004981), African in 118 of 24764 chromosomes (freq: 0.004765), South Asian in 136 of 30462 chromosomes (freq: 0.004465), and European (Finnish) in 110 of 25046 chromosomes (freq: 0.004392). The p.Leu441 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2016	The L441P variant in the PRODH gene has been reported previously in association with hyperprolinemia type I (Jacquet et al., 2002). The NHLBI ESP Exome Sequencing Project reports L441P was observed in 58/8600 alleles from individuals of European-American background, with no homozygous individuals reported. The L441P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Functional studies show that the L441P variant leads to reduced stability of proline oxidase and significant reduction in its activity (Bender et al., 2005). The L441P variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Schizophrenia 4

Pathogenic:1Other:1

risk factor, no assertion criteria provided	literature only	OMIM	Mar 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 27, 2020	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM3,PP4. This variant was detected in homozygous state. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2020

The c.1322T>C (p.L441P) alteration is located in exon 12 (coding exon 11) of the PRODH gene. This alteration results from a T to C substitution at nucleotide position 1322, causing the leucine (L) at amino acid position 441 to be replaced by a proline (P). Based on data from the Genome Aggregation Database (gnomAD) database, the PRODH c.1322T>C alteration was observed in 0.52% (1454/281208) of total alleles studied, with a frequency of 0.65% (231/35338) in the Latino subpopulation. This alteration has been reported in the homozygous state as well as in trans with other alterations in patients with hyperprolinemia who also had neurological symptoms (Jacquet, 2002; Afenjar, 2007; Guilmatre, 2010). This alteration was significantly associated with hyperprolinemia in a case-control study (Jacquet, 2005). This amino acid position is highly conserved in available vertebrate species. Functional studies demonstrate that this alteration results in a severe reduction of proline oxidase (POX) activity and reduced stability (Zhang, 2004; Bender, 2005). The in silico prediction for the p.L441P alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Proline dehydrogenase deficiency;C1833247:Schizophrenia 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

PS3+PM3+PP4 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 17, 2024

Variant summary: PRODH c.1322T>C (p.Leu441Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0052 in 249888 control chromosomes in the gnomAD database, including 12 homozygotes. c.1322T>C has been reported in the literature in individuals affected with Proline Dehydrogenase Deficiency, hyperprolinemia and autistic feature (example, Jacquet_2002, Minardi_2020, Raux_2007). These report(s) do not provide unequivocal conclusions about association of the variant with Proline Dehydrogenase Deficiency. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in less than 10% of enzymatic activity WT in vitro and inability to increase intracellular ROS levels (Nagano_2017). The following publications have been ascertained in the context of this evaluation (PMID: 12217952, 32725632, 28264926, 17135275). ClinVar contains an entry for this variant (Variation ID: 4008). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;.;.;T

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;.;D;.

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.067

T;T;T;T

MetaSVM

Uncertain

0.33

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.3

.;D;D;D

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

.;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

0.66

.;P;P;.

Vest4

0.99

MVP

0.71

MPC

0.91

ClinPred

0.11

GERP RS

4.5

gMVP

0.98

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