VCV000488487.58 - ClinVar

NM_016035.5(COQ4):c.437T>G (p.Phe146Cys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(10)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(6); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_016035.5(COQ4):c.437T>G (p.Phe146Cys)

Variation ID: 488487 Accession: VCV000488487.58

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q34.11 9: 128332187 (GRCh38) [ NCBI UCSC ] 9: 131094466 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 8, 2018	Oct 20, 2024	Jan 17, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_016035.5:c.437T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_057119.3:p.Phe146Cys	missense
NM_001305942.2:c.3-1287T>G		intron variant
NM_016035.4:c.[437T>G]
NC_000009.12:g.128332187T>G
NC_000009.11:g.131094466T>G
NG_042101.1:g.14680T>G

... more HGVS ... less HGVS

Protein change

F146C

Other names

Canonical SPDI

NC_000009.12:128332186:T:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA375022910 dbSNP: rs1163170578 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
COQ4		-	-	GRCh38 GRCh37	269	331

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome	Pathogenic/Likely pathogenic (7)	criteria provided, multiple submitters, no conflicts	Jan 17, 2022	RCV000578266.22
not provided	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Oct 23, 2020	RCV000659124.26
Abnormality of the nervous system	Likely pathogenic (1)	criteria provided, single submitter	Jul 10, 2021	RCV001814189.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Jan 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580760.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS4, PM3, PM2_SUP, PP3	Number of individuals with the variant: 2
Likely pathogenic (Dec 11, 2017)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV000680180.1 First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018	Sex: male Tissue: blood
Likely pathogenic (Dec 03, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome Affected status: yes Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000746530.1 First in ClinVar: Apr 28, 2018 Last updated: Apr 28, 2018	Age: 0-9 years Sex: female Geographic origin: Iran
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV001426599.1 First in ClinVar: Aug 09, 2020 Last updated: Aug 09, 2020	Publications: PubMed (1) PubMed: 32860008
Likely pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447366.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Mitochondrial encephalopathy (present) Sex: female
Likely pathogenic (Jul 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Abnormality of the nervous system Affected status: yes Allele origin: germline	Kariminejad - Najmabadi Pathology & Genetics Center Accession: SCV001755392.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV002073117.1 First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022	Comment: The missense variant p.F146C in COQ4 (NM_016035.5) has been previously reported (Bertoli-Avella AM et al). The variant has been submitted to ClinVar as Pathogenic/Likely pathogenic … (more) The missense variant p.F146C in COQ4 (NM_016035.5) has been previously reported (Bertoli-Avella AM et al). The variant has been submitted to ClinVar as Pathogenic/Likely pathogenic and Uncertain Significance. The p.F146C variant is observed in 1/2,25,000 (0.0004%) alleles from individuals of all background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.F146C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The phenylalanine residue at codon 146 of COQ4 is conserved in all mammalian species. The nucleotide c.437 in COQ4 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less) Clinical Features: Prolonged neonatal jaundice (present) , Spasticity (present) , Motor delay (present) , Micrognathia (present) , Mitochondrial depletion (present)
Uncertain significance (Mar 01, 2018)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000780938.29 First in ClinVar: Jul 09, 2018 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence, Accession: SCV001245480.1 First in ClinVar: May 09, 2020 Last updated: May 09, 2020	Sex: male
Uncertain significance (Jan 18, 2022)	Flagged submission flagged submission (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003304258.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 32860008‚ 33215859 Comment: 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 … (more) 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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 488487). This missense change has been observed in individuals with coenzyme Q10 deficiency (PMID: 32860008, 33215859). This variant is present in population databases (no rsID available, gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 146 of the COQ4 protein (p.Phe146Cys). (less)
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

The missense variant p.F146C in COQ4 (NM_016035.5) has been previously reported (Bertoli-Avella AM et al). The variant has been submitted to ClinVar as Pathogenic/Likely pathogenic and Uncertain Significance. The p.F146C variant is observed in 1/2,25,000 (0.0004%) alleles from individuals of all background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.F146C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The phenylalanine residue at codon 146 of COQ4 is conserved in all mammalian species. The nucleotide c.437 in COQ4 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.

Comment:

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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 488487). This missense change has been observed in individuals with coenzyme Q10 deficiency (PMID: 32860008, 33215859). This variant is present in population databases (no rsID available, gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 146 of the COQ4 protein (p.Phe146Cys).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical spectrum in multiple families with primary COQ(10) deficiency.	Hashemi SS	American journal of medical genetics. Part A	2021	PMID: 33215859
Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.	Bertoli-Avella AM	European journal of human genetics : EJHG	2021	PMID: 32860008

Text-mined citations for rs1163170578 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_016035.5(COQ4):c.437T>G (p.Phe146Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1163170578 ...