NM_001875.5(CPS1):c.2623A>G (p.Lys875Glu) AND Congenital hyperammonemia, type I

Germline classification:: Benign (3 submissions)
Last evaluated:: Feb 1, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000871416.13

Allele description [Variation Report for NM_001875.5(CPS1):c.2623A>G (p.Lys875Glu)]

NM_001875.5(CPS1):c.2623A>G (p.Lys875Glu)

Gene:

CPS1:carbamoyl-phosphate synthase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q34

Genomic location:

Preferred name:

NM_001875.5(CPS1):c.2623A>G (p.Lys875Glu)

HGVS:

NC_000002.12:g.210616477A>G
NG_008285.1:g.143793A>G
NM_001122633.3:c.2623A>G
NM_001369256.1:c.2656A>G
NM_001369257.1:c.2623A>G
NM_001875.5:c.2623A>GMANE SELECT
NP_001116105.2:p.Lys875Glu
NP_001356185.1:p.Lys886Glu
NP_001356186.1:p.Lys875Glu
NP_001866.2:p.Lys875Glu
LRG_336t1:c.2623A>G
LRG_336:g.143793A>G
NC_000002.11:g.211481201A>G
NM_001875.4:c.2623A>G
NR_161225.1:n.3532A>G
NR_163592.1:n.1779A>G

Protein change:

K875E

Links:

dbSNP: rs147062907

NCBI 1000 Genomes Browser:

rs147062907

Molecular consequence:

NM_001122633.3:c.2623A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369256.1:c.2656A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369257.1:c.2623A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001875.5:c.2623A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_161225.1:n.3532A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_163592.1:n.1779A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Congenital hyperammonemia, type I
Synonyms:: CPS I DEFICIENCY; Hyperammonemia due to carbamoyl phosphate synthetase 1 deficiency; CPS 1 deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009376; MedGen: C4082171; Orphanet: 147; OMIM: 237300

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001013075	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Feb 1, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001435150	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign	germline	research	PubMed (3) [See all records that cite these PMIDs] 15164414, 24813853, 25741868
SCV002076249	Natera, Inc.	no assertion criteria provided	Benign (Apr 26, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001013075

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Benign
(Feb 1, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001435150

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Benign

germline

research

PubMed (3)
[See all records that cite these PMIDs]

SCV002076249

Natera, Inc.

no assertion criteria provided

Benign
(Apr 26, 2020)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Genetic approach to prenatal diagnosis in urea cycle defects.

Häberle J, Koch HG.

Prenat Diagn. 2004 May;24(5):378-83.

PubMed [citation]

PMID:: 15164414

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001013075.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001435150.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (3)

Description

The heterozygous p.Lys875Glu variant in CPS1 has been identified in an individual with carbamoyl phosphate synthetase I deficiency and in cis with a missense variant that may cause disease (PMID: 15164414), and has also been identified in >1% of South Asian chromosomes and 8 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Lys875Glu variant may not impact protein function (PMID: 24813853). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for carbamoyl phosphate synthetase I deficiency.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002076249.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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