NM_001875.5(CPS1):c.1315G>A (p.Gly439Arg) AND Congenital hyperammonemia, type I

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 8, 2022
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:: RCV001808268.7

Allele description [Variation Report for NM_001875.5(CPS1):c.1315G>A (p.Gly439Arg)]

NM_001875.5(CPS1):c.1315G>A (p.Gly439Arg)

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.1315G>A (p.Gly439Arg)

HGVS:

NC_000002.12:g.210595538G>A
NG_008285.1:g.122854G>A
NM_001122633.3:c.1315G>A
NM_001369256.1:c.1348G>A
NM_001369257.1:c.1315G>A
NM_001875.5:c.1315G>AMANE SELECT
NP_001116105.2:p.Gly439Arg
NP_001356185.1:p.Gly450Arg
NP_001356186.1:p.Gly439Arg
NP_001866.2:p.Gly439Arg
LRG_336:g.122854G>A
NC_000002.11:g.211460262G>A
NR_161225.1:n.2227G>A
NR_163592.1:n.471G>A

Protein change:

G439R

Links:

dbSNP: rs2106118268

NCBI 1000 Genomes Browser:

rs2106118268

Molecular consequence:

NM_001122633.3:c.1315G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369256.1:c.1348G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369257.1:c.1315G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001875.5:c.1315G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_161225.1:n.2227G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_163592.1:n.471G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

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
SCV002058918	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002164180	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 8, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002058918

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 3, 2022)

germline

clinical testing

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

SCV002164180

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 8, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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

Details of each submission

From 3billion, SCV002058918.1

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

Description

The variant not observed in the gnomAD v2.1.1 dataset (PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.949, 3CNET: 0.954, PP3_P). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002164180.3

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

Description

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. 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. ClinVar contains an entry for this variant (Variation ID: 1333580). This variant has not been reported in the literature in individuals affected with CPS1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 439 of the CPS1 protein (p.Gly439Arg).

#	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: Sep 29, 2024

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