NM_001358921.2(COQ2):c.310G>A (p.Gly104Ser) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Oct 31, 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:: RCV000508587.15

Allele description [Variation Report for NM_001358921.2(COQ2):c.310G>A (p.Gly104Ser)]

NM_001358921.2(COQ2):c.310G>A (p.Gly104Ser)

Gene:

COQ2:coenzyme Q2, polyprenyltransferase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q21.23

Genomic location:

Preferred name:

NM_001358921.2(COQ2):c.310G>A (p.Gly104Ser)

HGVS:

NC_000004.12:g.83279058C>T
NG_015825.1:g.10857G>A
NM_001358921.2:c.310G>AMANE SELECT
NM_015697.9:c.460G>A
NP_001345850.1:p.Gly104Ser
NP_056512.5:p.Gly154Ser
NC_000004.11:g.84200211C>T
NM_015697.7:c.460G>A
NM_015697.8:c.460G>A

Protein change:

G104S

Links:

dbSNP: rs146983090

NCBI 1000 Genomes Browser:

rs146983090

Molecular consequence:

NM_001358921.2:c.310G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_015697.9:c.460G>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
SCV000603217	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (May 5, 2017)	germline	clinical testing	Citation Link,
SCV002271808	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002601149	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Oct 31, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000603217

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Uncertain significance
(May 5, 2017)

germline

clinical testing

Citation Link,

SCV002271808

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 22, 2022)

germline

clinical testing

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

SCV002601149

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Oct 31, 2022)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
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

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000603217.2

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

Description

The p.Gly154Ser variant (rs146983090) has not been reported in the medical literature, is not listed in gene-specific variant databases, nor has it been previously identified in our laboratory. It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in African populations of 0.13% (identified in 29 out of 21,834 chromosomes). The glycine at codon 154 is highly conserved considering 12 species up to C. elegans (Alamut software v2.9), and computational analyses suggest this variant has a significant effect on COQ2 protein structure/function (SIFT: damaging, PolyPhen2: possibly damaging, and Mutation Taster: disease causing). Additionally, variants affecting two other nearby variants (c.440T>C; p.Ile147Thr and c.469C>T; p.Pro157Ser) were found in a cohort of multiple-system atrophy patients and both were shown to disrupt COQ2 protein function using enzyme activity/yeast complementation assays (Mitsui 2013); suggesting this region of COQ2 is critical for function. However, based on the available information, the clinical significance of the p.Gly154Ser variant cannot be determined with certainty.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002271808.2

#	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 glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 154 of the COQ2 protein (p.Gly154Ser). This variant is present in population databases (rs146983090, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with COQ2-related conditions. ClinVar contains an entry for this variant (Variation ID: 439551). 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, SCV002601149.2

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

#	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: Sep 29, 2024

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