NM_018714.3(COG1):c.1757G>A (p.Arg586Gln) AND COG1 congenital disorder of glycosylation

Clinical significance:Uncertain significance (Last evaluated: Jun 7, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001128422.2

Allele description [Variation Report for NM_018714.3(COG1):c.1757G>A (p.Arg586Gln)]

NM_018714.3(COG1):c.1757G>A (p.Arg586Gln)

Gene:
COG1:component of oligomeric golgi complex 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17q25.1
Genomic location:
Preferred name:
NM_018714.3(COG1):c.1757G>A (p.Arg586Gln)
HGVS:
  • NC_000017.11:g.73201584G>A
  • NG_008971.1:g.13551G>A
  • NM_018714.3:c.1757G>AMANE SELECT
  • NP_061184.1:p.Arg586Gln
  • NC_000017.10:g.71197723G>A
  • NM_018714.2:c.1757G>A
Protein change:
R586Q
Links:
Molecular consequence:
  • NM_018714.3:c.1757G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
COG1 congenital disorder of glycosylation (CDG2G)
Synonyms:
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIg; CDG IIg; CDGII/COG1 CEREBROCOSTOMANDIBULAR-LIKE SYNDROME; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0012637; MedGen: C2931011; Orphanet: 263508; OMIM: 611209

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001287864Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Jan 12, 2018)
germlineclinical testing

Citation Link,

SCV001545169Invitaecriteria provided, single submitter
Uncertain significance
(Jun 7, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Illumina Clinical Services Laboratory,Illumina, SCV001287864.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001545169.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change replaces arginine with glutamine at codon 586 of the COG1 protein (p.Arg586Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs769310036, ExAC 0.02%). This variant has not been reported in the literature in individuals with COG1-related conditions. 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 glutamine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 28, 2021

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