NM_001875.5(CPS1):c.3643A>G (p.Ile1215Val) AND Congenital hyperammonemia, type I

replaced

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 2, 2018
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000655210.2

Allele description

NM_001875.5(CPS1):c.3643A>G (p.Ile1215Val)

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.3643A>G (p.Ile1215Val)

HGVS:

NC_000002.12:g.210656609A>G
NG_008285.1:g.183925A>G
NM_001122633.3:c.3643A>G
NM_001369256.1:c.3676A>G
NM_001369257.1:c.3643A>G
NM_001875.5:c.3643A>G
NP_001116105.2:p.Ile1215Val
NP_001356185.1:p.Ile1226Val
NP_001356186.1:p.Ile1215Val
NP_001866.2:p.Ile1215Val
LRG_336t1:c.3643A>G
LRG_336:g.183925A>G
NC_000002.11:g.211521333A>G
NM_001875.4:c.3643A>G
NR_161225.1:n.4552A>G
NR_163592.1:n.2799A>G
P31327:p.Ile1215Val

Protein change:

I1215V

Links:

UniProtKB: P31327#VAR_063574; dbSNP: rs141373204

NCBI 1000 Genomes Browser:

rs141373204

Molecular consequence:

NM_001122633.3:c.3643A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369256.1:c.3676A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369257.1:c.3643A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001875.5:c.3643A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_161225.1:n.4552A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_163592.1:n.2799A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Congenital hyperammonemia, type I
Synonyms:: CPS I DEFICIENCY; Carbamoyl phosphate synthetase 1 deficiency
Identifiers:: MedGen: C4082171; Orphanet: 147; OMIM: 237300

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000777135	Invitae	criteria provided, single submitter (Nykamp K et al. (Genet Med 2017))	Uncertain significance (Apr 2, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17310273, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000777135

Invitae

criteria provided, single submitter

(Nykamp K et al. (Genet Med 2017))

Uncertain significance
(Apr 2, 2018)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Molecular and clinical analyses of Japanese patients with carbamoylphosphate synthetase 1 (CPS1) deficiency.

Kurokawa K, Yorifuji T, Kawai M, Momoi T, Nagasaka H, Takayanagi M, Kobayashi K, Yoshino M, Kosho T, Adachi M, Otsuka H, Yamamoto S, Murata T, Suenaga A, Ishii T, Terada K, Shimura N, Kiwaki K, Shintaku H, Yamakawa M, Nakabayashi H, Wakutani Y, et al.

J Hum Genet. 2007;52(4):349-354. doi: 10.1007/s10038-007-0122-9. Epub 2007 Feb 20.

PubMed [citation]

PMID:: 17310273

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000777135.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces isoleucine with valine at codon 1215 of the CPS1 protein (p.Ile1215Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs141373204, ExAC 0.3%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with carbamoylphosphate synthetase I deficiency in combination with a pathogenic CPS1 variant (PMID: 17310273). ClinVar contains an entry for this variant (Variation ID: 235659). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

#	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: Nov 2, 2019

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