rs2904551

Variant names:

• chr22-18918421-A-G
• rs2904551
• NM_016335.6:c.1322T>C

Your query was ambiguous. Multiple possible variants found:

• chr22-18918421-A-G
• chr22-18918421-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PS1_Moderate PP5 BP4 BS1_Supporting BS2

The NM_016335.6(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 the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 3)
  • Exomes 𝑓: 0.0039 (50 hom.)
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:9 O:1
• Conservation: PhyloP100: 6.87

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]

ENSG00000283809 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PS1: Transcript NM_016335.6 (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=5, Uncertain_significance=7, Pathogenic=2}. 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.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00253 (29/11484) while in subpopulation EAS AF= 0.00446 (3/672). AF 95% confidence interval is 0.0015. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 3. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 50 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRODH	NM_016335.6	c.1322T>C	p.Leu441Pro	missense_variant	Exon 11 of 14	ENST00000357068.11	NP_057419.5
PRODH	NM_001195226.2	c.998T>C	p.Leu333Pro	missense_variant	Exon 11 of 14		NP_001182155.2
PRODH	NM_001368250.2	c.998T>C	p.Leu333Pro	missense_variant	Exon 11 of 14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11	c.1322T>C	p.Leu441Pro	missense_variant	Exon 11 of 14	1	NM_016335.6	ENSP00000349577.6
ENSG00000283809	ENST00000638240.1	c.513+7393A>G		intron_variant	Intron 4 of 5	5		ENSP00000492446.1

Frequencies

GnomAD3 genomes AF: 0.00253 AC: 29 AN: 11466 Hom.: 0 Cov.: 3

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.: 12 AF XY: 0.00507 AC XY: 686 AN XY: 135246

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.: 50 Cov.: 0 AF XY: 0.00387 AC XY: 388 AN XY: 100218

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: 29 AN: 11484 Hom.: 0 Cov.: 3 AF XY: 0.00197 AC XY: 10 AN XY: 5078

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.: 1

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.00674 AC: 58

ExAC AF: 0.00575 AC: 698

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:9 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Proline dehydrogenase deficiency Pathogenic:2 Uncertain:6

Apr 01, 2023

Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 29, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 20, 2025

Department of Human Genetics, Hannover Medical School

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG: BS2, PS3_Supporting, PP4_Strong -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 29, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 37803864). ClinVar contains an entry for this variant (Variation ID: 4008). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PRODH protein function with a positive predictive value of 80%. 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. -

not provided Pathogenic:3 Uncertain:1

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PRODH: PM3, PM2:Supporting, PP3, PP4, PS3:Supporting -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Mar 15, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 19, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Proline dehydrogenase deficiency;C1833247:Schizophrenia 4 Pathogenic:1 Uncertain:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3+PM3+PP4 -

Apr 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Schizophrenia 4 Pathogenic:1 Other:1

Jan 27, 2020

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 01, 2005

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1

Dec 28, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Uncertain:1

Nov 22, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PRODH c.1322T>C (p.Leu441Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0038 in 202168 control chromosomes in the gnomAD database, including 50 homozygotes. The observed variant frequency exceeds the estimated maximal expected allele frequency for a pathogenic variant in PRODH causing Proline Dehydrogenase Deficiency phenotype, providing evidence for a benign role. However, c.1322T>C has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Hyperprolinemia type 1 (e.g. Jacquet_2002, Raux_2010, Guilmatre_2010, Cho_2017, Ong_2023, Zhang_2024), in heterozygous individuals affected with schizophrenia (e.g. Jacquet_2002) or in compound heterozygous individuals unaffected with Hyperprolinemia type 1 (e.g. Chen_2023, Tang_2024). These data collectively suggest the variant may be a risk factor associated with disease. In multiple reports evaluating variant impact on protein function, null residual enzyme activity of the variant was reported in vitro or in a homozygous hyperprolinemia patient (e.g. Bender_2005, Guilmatre_2010) or additionally showed an inability to increase intracellular ROS levels compared to WT (e.g. Nagano_2017). The following publications have been ascertained in the context of this evaluation (PMID: 15662599, 37656460, 28851938, 20524212, 12217952, 32725632, 28264926, 37636236, 17135275, 38651393, 37147621). ClinVar contains an entry for this variant (Variation ID: 4008). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.;.;T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;.;D;.
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.067	T;T;T;T
MetaSVM	Uncertain	0.33	D
PrimateAI	Uncertain	0.72	T
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	T
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

Other links and lift over

dbSNP: rs2904551; hg19: chr22-18905934;