VCV000557195.9 - ClinVar

NM_001875.5(CPS1):c.2809_2810del (p.Ile937fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(2); Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001875.5(CPS1):c.2809_2810del (p.Ile937fs)

Variation ID: 557195 Accession: VCV000557195.9

Type and length

Deletion, 2 bp

Location

Cytogenetic: 2q34 2: 210637823-210637824 (GRCh38) [ NCBI UCSC ] 2: 211502547-211502548 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 5, 2018	Feb 14, 2024	Feb 3, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001875.5:c.2809_2810del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001866.2:p.Ile937fs	frameshift
NM_001875.5:c.2809_2810delAT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001122633.3:c.2809_2810del	NP_001116105.2:p.Ile937fs	frameshift
NM_001369256.1:c.2842_2843del	NP_001356185.1:p.Ile948fs	frameshift
NM_001369257.1:c.2809_2810del	NP_001356186.1:p.Ile937fs	frameshift
NR_161225.1:n.3718_3719del		non-coding transcript variant
NR_163592.1:n.1965_1966del		non-coding transcript variant
NC_000002.12:g.210637823_210637824del
NC_000002.11:g.211502547_211502548del
NG_008285.1:g.165139_165140del
LRG_336:g.165139_165140del
LRG_336t1:c.2809_2810del

... more HGVS ... less HGVS

Protein change

I937fs, I948fs

Other names

Canonical SPDI

NC_000002.12:210637822:AT:

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

Links

dbSNP: rs1318756445 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CPS1		-	-	GRCh38 GRCh37	1962	1993

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Congenital hyperammonemia, type I	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Feb 3, 2023	RCV000673303.9
Pulmonary hypertension, neonatal, susceptibility to	Pathogenic (1)	criteria provided, single submitter	Oct 12, 2022	RCV003465526.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Mar 12, 2018)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Congenital hyperammonemia, type I Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000798487.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (1) PubMed: 21120950
Uncertain significance (Nov 01, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Congenital hyperammonemia, type I Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000914890.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (1) PubMed: 21120950 Comment: The CPS1 c.2809_2810delAT (p.Ile937ProfsTer5) variant results in a frameshift, and is predicted to result in premature termination of the protein. A literature search was performed … (more) The CPS1 c.2809_2810delAT (p.Ile937ProfsTer5) variant results in a frameshift, and is predicted to result in premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. The p.Ile937ProfsTer5 variant is listed in a supplementary table in Haberle et al. (2011) as a novel variant, with no further details given. This variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium or the Genome Aggregation Database in a region of good coverage, so the variant is presumed to be rare. Based on the predicted truncating nature of the variant and limited evidence, the p.Ile937ProfsTer5 variant is classified as a variant of unknown significance but suspicious for pathogenicity for carbamoylphosphate synthetase I deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Oct 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pulmonary hypertension, neonatal, susceptibility to Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004216196.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Feb 03, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Congenital hyperammonemia, type I Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004293068.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 21120950 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 557195). This premature translational stop signal … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 557195). This premature translational stop signal has been observed in individual(s) with carbamoyl phosphate synthetase I deficiency (PMID: 21120950). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Ile937Profs*5) in the CPS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CPS1 are known to be pathogenic (PMID: 21120950). (less)
not provided (-)	no classification provided Method: phenotyping only	Congenital hyperammonemia, type I Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV004228704.1 First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024	Comment: Variant interpreted as Likely pathogenic and reported on 04-20-2020 by Lab Natera. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the … (more) Variant interpreted as Likely pathogenic and reported on 04-20-2020 by Lab Natera. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Abnormality of eye movement (present) , Hypermetropia (present) , Vertigo (present) , Hyperacusis (present) , Tinnitus (present) , Abnormal oral cavity morphology (present) , Atrophic … (more) Abnormality of eye movement (present) , Hypermetropia (present) , Vertigo (present) , Hyperacusis (present) , Tinnitus (present) , Abnormal oral cavity morphology (present) , Atrophic scars (present) , Hyperpigmentation of the skin (present) , Thickened skin (present) , Abnormality of the cardiovascular system (present) , Autoimmunity (present) , Immunodeficiency (present) , Abnormal inflammatory response (present) , Abnormal stomach morphology (present) , Abnormal muscle physiology (present) , Abnormality of the somatic nervous system (present) , Abnormality of the musculature of the limbs (present) , Abnormal morphology of the pelvis musculature (present) , Abnormal curvature of the vertebral column (present) , Abnormality of reproductive system physiology (present) , Abnormality of urine homeostasis (present) , Anxiety (present) , Depression (present) , Motor stereotypies (present) (less) Indication for testing: Carrier Screening Age: 20-29 years Sex: female Method: Gene Panel Sequencing Testing laboratory: Natera, Inc. Date variant was reported to submitter: 2020-04-20 Testing laboratory interpretation: Likely pathogenic

Comment:

The CPS1 c.2809_2810delAT (p.Ile937ProfsTer5) variant results in a frameshift, and is predicted to result in premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. The p.Ile937ProfsTer5 variant is listed in a supplementary table in Haberle et al. (2011) as a novel variant, with no further details given. This variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium or the Genome Aggregation Database in a region of good coverage, so the variant is presumed to be rare. Based on the predicted truncating nature of the variant and limited evidence, the p.Ile937ProfsTer5 variant is classified as a variant of unknown significance but suspicious for pathogenicity for carbamoylphosphate synthetase I deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 557195). This premature translational stop signal has been observed in individual(s) with carbamoyl phosphate synthetase I deficiency (PMID: 21120950). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Ile937Profs*5) in the CPS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CPS1 are known to be pathogenic (PMID: 21120950).

Comment:

Variant interpreted as Likely pathogenic and reported on 04-20-2020 by Lab Natera. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Molecular defects in human carbamoy phosphate synthetase I: mutational spectrum, diagnostic and protein structure considerations.	Häberle J	Human mutation	2011	PMID: 21120950

Text-mined citations for rs1318756445 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001875.5(CPS1):c.2809_2810del (p.Ile937fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1318756445 ...