rs1553512642

Positions:

• chr2-210602254-G-A
• chr2-210602254-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001875.5(CPS1):​c.1760G>A​(p.Arg587His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R587C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: CPS1 NM_001875.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.60

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a domain ATP-grasp 1 (size 192) in uniprot entity CPSM_HUMAN there are 43 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 2-210602254-G-A is Pathogenic according to our data. Variant chr2-210602254-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 549934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210602254-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPS1	NM_001875.5	c.1760G>A	p.Arg587His	missense_variant	16/38	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10	c.1760G>A	p.Arg587His	missense_variant	16/38	1	NM_001875.5	ENSP00000233072	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460526 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726600

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital hyperammonemia, type I Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 08, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 587 of the CPS1 protein (p.Arg587His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with carbamoyl phosphate synthetase I deficiency (PMID: 9686343, 20855223, 27150549, 31749211). ClinVar contains an entry for this variant (Variation ID: 549934). 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. Experimental studies have shown that this missense change affects CPS1 function (PMID: 15876373). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 21, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 26, 2021	Variant summary: CPS1 c.1760G>A (p.Arg587His) results in a non-conservative amino acid change located in the Carbamoyl-phosphate synthetase large subunit-like, ATP-binding domain (IPR005479) of 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 250578 control chromosomes (gnomAD). c.1760G>A has been reported in the literature in individuals affected with Carbamoylphosphate Synthetase I Deficiency, including one homozygote (Summar_1998, Kurokawa_2007, Wang_2010, Fan_2019). These data indicate that the variant is likely to be associated with disease. At least one functional study reports this variant affects the residue of the catalytic site and has been shown to practically abolished enzyme activity by blocking carbamate synthesis (Yefimenko_2005). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;D;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.2	.;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.9	D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.99
MutPred		0.94		.;Gain of sheet (P = 0.0827);.;
MVP		0.97
MPC		0.87
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.97
gMVP		0.97

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: rs1553512642; hg19: chr2-211466978; COSMIC: COSV51805942; COSMIC: COSV51805942;