NM_004341.5(CAD):c.6365G>A (p.Arg2122His) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 25, 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:: RCV001234151.8

Allele description [Variation Report for NM_004341.5(CAD):c.6365G>A (p.Arg2122His)]

NM_004341.5(CAD):c.6365G>A (p.Arg2122His)

Genes:

LOC126806172:CDK7 strongly-dependent group 2 enhancer GRCh37_chr2:27465505-27466704 [Gene]
CAD:carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p23.3

Genomic location:

Preferred name:

NM_004341.5(CAD):c.6365G>A (p.Arg2122His)

HGVS:

NC_000002.12:g.27242762G>A
NG_046394.1:g.30373G>A
NM_001306079.2:c.6176G>A
NM_004341.5:c.6365G>AMANE SELECT
NP_001293008.1:p.Arg2059His
NP_004332.2:p.Arg2122His
NC_000002.11:g.27465630G>A
NM_004341.3:c.6365G>A
NM_004341.4:c.6365G>A

Protein change:

R2059H

Links:

dbSNP: rs553324190

NCBI 1000 Genomes Browser:

rs553324190

Molecular consequence:

NM_001306079.2:c.6176G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004341.5:c.6365G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001406781	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 25, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001997877	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Oct 13, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001406781

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 25, 2022)

germline

clinical testing

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

SCV001997877

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Oct 13, 2019)

germline

clinical testing

Citation Link

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
not provided	germline	yes	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

Details of each submission

From Invitae, SCV001406781.4

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

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2122 of the CAD protein (p.Arg2122His). This variant is present in population databases (rs553324190, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CAD-related conditions. ClinVar contains an entry for this variant (Variation ID: 960599). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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

From GeneDx, SCV001997877.2

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

Description

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function

#	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

Last Updated: Mar 16, 2024

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