NM_016035.5(COQ4):c.437T>G (p.Phe146Cys) AND Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome

Germline classification:: Conflicting interpretations of pathogenicity (7 submissions)
Last evaluated:: Jan 18, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000578266.19

Allele description [Variation Report for NM_016035.5(COQ4):c.437T>G (p.Phe146Cys)]

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

Gene:

COQ4:coenzyme Q4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q34.11

Genomic location:

Preferred name:

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

HGVS:

NC_000009.12:g.128332187T>G
NG_042101.1:g.14680T>G
NM_001305942.2:c.3-1287T>G
NM_016035.5:c.437T>GMANE SELECT
NP_057119.3:p.Phe146Cys
NC_000009.11:g.131094466T>G
NM_016035.3:c.437T>G
NM_016035.4:c.437T>G
NM_016035.4:c.[437T>G]

Protein change:

F146C

Links:

dbSNP: rs1163170578

NCBI 1000 Genomes Browser:

rs1163170578

Molecular consequence:

NM_001305942.2:c.3-1287T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_016035.5:c.437T>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome
Synonyms:: Coenzyme Q10 deficiency, primary, 7
Identifiers:: MONDO: MONDO:0014562; MedGen: C5568562; Orphanet: 457185; OMIM: 616276

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000680180	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Likely pathogenic (Dec 11, 2017)	germline	clinical testing	Citation Link,
SCV000746530	Genomic Research Center, Shahid Beheshti University of Medical Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 3, 2017)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001245480	Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence,	no assertion criteria provided	Uncertain significance	inherited	clinical testing
SCV001426599	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 32860008
SCV002073117	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002580760	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 17, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003304258	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 18, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32860008, 33215859, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	3	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.

Bertoli-Avella AM, Beetz C, Ameziane N, Rocha ME, Guatibonza P, Pereira C, Calvo M, Herrera-Ordonez N, Segura-Castel M, Diego-Alvarez D, Zawada M, Kandaswamy KK, Werber M, Paknia O, Zielske S, Ugrinovski D, Warnack G, Kampe K, Iurașcu MI, Cozma C, Vogel F, Alhashem A, et al.

Eur J Hum Genet. 2021 Jan;29(1):141-153. doi: 10.1038/s41431-020-00713-9. Epub 2020 Aug 28.

PubMed [citation]

PMID:: 32860008
PMCID:: PMC7852664

See all PubMed Citations (4)

Details of each submission

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV000680180.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	blood	not provided		1	not provided	not provided	not provided

From Genomic Research Center, Shahid Beheshti University of Medical Sciences, SCV000746530.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence,, SCV001245480.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centogene AG - the Rare Disease Company, SCV001426599.1

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

#	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

From Neuberg Centre For Genomic Medicine, NCGM, SCV002073117.1

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

Description

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.

#	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

From MGZ Medical Genetics Center, SCV002580760.1

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

#	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		2	not provided	not provided	not provided

From Invitae, SCV003304258.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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).

#	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: May 12, 2024

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