2-210647986-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_001875.5(CPS1):​c.3265C>T​(p.Arg1089Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,888 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1089H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CPS1
NM_001875.5 missense

Scores

17
1
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 4.49
Variant links:
Genes affected
CPS1 (HGNC:2323): (carbamoyl-phosphate synthase 1) The mitochondrial enzyme encoded by this gene catalyzes synthesis of carbamoyl phosphate from ammonia and bicarbonate. This reaction is the first committed step of the urea cycle, which is important in the removal of excess urea from cells. The encoded protein may also represent a core mitochondrial nucleoid protein. Three transcript variants encoding different isoforms have been found for this gene. The shortest isoform may not be localized to the mitochondrion. Mutations in this gene have been associated with carbamoyl phosphate synthetase deficiency, susceptibility to persistent pulmonary hypertension, and susceptibility to venoocclusive disease after bone marrow transplantation.[provided by RefSeq, May 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1
In a helix (size 9) in uniprot entity CPSM_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_001875.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-210647987-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2994736.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant 2-210647986-C-T is Pathogenic according to our data. Variant chr2-210647986-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 551329.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}. Variant chr2-210647986-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CPS1NM_001875.5 linkc.3265C>T p.Arg1089Cys missense_variant Exon 26 of 38 ENST00000233072.10 NP_001866.2 P31327-1A0A024R454Q6PEK7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CPS1ENST00000233072.10 linkc.3265C>T p.Arg1089Cys missense_variant Exon 26 of 38 1 NM_001875.5 ENSP00000233072.5 P31327-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152174
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461714
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727164
show subpopulations
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
AF:
0.00000657
AC:
1
AN:
152174
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Congenital hyperammonemia, type I Pathogenic:2Uncertain:1
Apr 06, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1089 of the CPS1 protein (p.Arg1089Cys). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with CPS1-related conditions (PMID: 21120950, 33309754). ClinVar contains an entry for this variant (Variation ID: 551329). 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 CPS1 protein function. This variant disrupts the p.Arg1089 amino acid residue in CPS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15876373, 16737834). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Apr 04, 2017
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 17, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: CPS1 c.3265C>T (p.Arg1089Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251266 control chromosomes. c.3265C>T has been observed in the presumed homozygous or compound heterozygous state in at least 2 individual(s) affected with clinical features of Carbamoylphosphate Synthetase I Deficiency (example, Makris_2021, Khayat_2009, Haberle_2011). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Additionally, a different missense variant at this codon has been reported to be likely pathogenic/pathogenic at Labcorp (c.3266G>T, p.Arg1089Leu), supporting the critical relevance of codon 1089 for CPS1 protein function. The following publications have been ascertained in the context of this evaluation (PMID: 21120950, 33309754, 19309799, 33551825, 31839005, 31507628, 26214590, 20852892, 20800523, 19092443, 15876373, 16737834). ClinVar contains an entry for this variant (Variation ID: 551329). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Uncertain:1
Jan 29, 2020
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in two individuals from a cohort of patients with CPS1 deficiency, however specific clinical information on patients was not provided, nor was the presence of a second variant in CPS1 discussed (Haberle et al., 2011); This variant is associated with the following publications: (PMID: 20800523, 21120950, 19092443, 19309799) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.98
.;D;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.95
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
D;D;D
M_CAP
Pathogenic
0.56
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.9
.;H;.
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-7.7
D;D;D
REVEL
Pathogenic
0.90
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
.;D;.
Vest4
0.97
MutPred
0.97
.;Loss of disorder (P = 0.0182);.;
MVP
0.98
MPC
0.99
ClinPred
1.0
D
GERP RS
6.0
Varity_R
0.96
gMVP
0.93

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.

Other links and lift over

dbSNP: rs1392559810; hg19: chr2-211512710; COSMIC: COSV51802375; COSMIC: COSV51802375; API