VCV000214235.12 - ClinVar

NM_182476.3(COQ6):c.436G>T (p.Asp146Tyr)

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.

(5)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_182476.3(COQ6):c.436G>T (p.Asp146Tyr)

Variation ID: 214235 Accession: VCV000214235.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q24.3 14: 73955883 (GRCh38) [ NCBI UCSC ] 14: 74422586 (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	Oct 11, 2015	May 1, 2024	Aug 3, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_182476.3:c.436G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_872282.1:p.Asp146Tyr	missense
NM_001382258.1:c.1201-296C>A		intron variant
NM_001382262.1:c.1201-55C>A		intron variant
NM_001425255.1:c.436G>T	NP_001412184.1:p.Asp146Tyr	missense
NM_001425256.1:c.436G>T	NP_001412185.1:p.Asp146Tyr	missense
NM_001425257.1:c.271G>T	NP_001412186.1:p.Asp91Tyr	missense
NM_001425258.1:c.361G>T	NP_001412187.1:p.Asp121Tyr	missense
NM_001425259.1:c.211G>T	NP_001412188.1:p.Asp71Tyr	missense
NM_001425260.1:c.211G>T	NP_001412189.1:p.Asp71Tyr	missense
NM_001425261.1:c.211G>T	NP_001412190.1:p.Asp71Tyr	missense
NM_001425262.1:c.357+374G>T		intron variant
NM_001425263.1:c.109G>T	NP_001412192.1:p.Asp37Tyr	missense
NM_001425264.1:c.27G>T	NP_001412193.1:p.Met9Ile	missense
NM_001425265.1:c.27G>T	NP_001412194.1:p.Met9Ile	missense
NM_182480.3:c.361G>T	NP_872286.2:p.Asp121Tyr	missense
NC_000014.9:g.73955883G>T
NC_000014.8:g.74422586G>T
NG_032805.1:g.10950G>T

... more HGVS ... less HGVS

Protein change

D121Y, D146Y

Other names

p.D146Y:GAT>TAT

Canonical SPDI

NC_000014.9:73955882:G:T

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) 0.00014

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

Exome Aggregation Consortium (ExAC) 0.00007

The Genome Aggregation Database (gnomAD), exomes 0.00008

Trans-Omics for Precision Medicine (TOPMed) 0.00012

Links

ClinGen: CA325057 dbSNP: rs140725181 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.
COQ6		-	-	GRCh38 GRCh37	70	319
ENTPD5		-	-	GRCh38 GRCh37	23	256

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.
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 3, 2022	RCV000200480.15
Familial steroid-resistant nephrotic syndrome with sensorineural deafness	Uncertain significance (2)	criteria provided, single submitter	Feb 23, 2022	RCV002503769.9
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Jul 11, 2022	RCV002515386.9

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.
Uncertain significance (Oct 31, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000251272.10 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Comment: In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our … (more) In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge (less)
Uncertain significance (Feb 23, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial steroid-resistant nephrotic syndrome with sensorineural deafness Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002815727.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Aug 03, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002152039.2 First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023	Comment: This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 146 of the COQ6 protein … (more) This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 146 of the COQ6 protein (p.Asp146Tyr). This variant is present in population databases (rs140725181, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with COQ6-related conditions. ClinVar contains an entry for this variant (Variation ID: 214235). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. (less)
Uncertain significance (Jul 11, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003742655.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Comment: The c.436G>T (p.D146Y) alteration is located in exon 4 (coding exon 4) of the COQ6 gene. This alteration results from a G to T substitution … (more) The c.436G>T (p.D146Y) alteration is located in exon 4 (coding exon 4) of the COQ6 gene. This alteration results from a G to T substitution at nucleotide position 436, causing the aspartic acid (D) at amino acid position 146 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
not provided (-)	no classification provided Method: phenotyping only	Familial steroid-resistant nephrotic syndrome with sensorineural deafness Affected status: unknown Allele origin: unknown	GenomeConnect - Brain Gene Registry Accession: SCV004032166.1 First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023	Comment: Variant interpreted as Uncertain significance and reported on 11-20-2013 by Lab GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. … (more) Variant interpreted as Uncertain significance and reported on 11-20-2013 by Lab GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less) Clinical Features: Obesity (present) , Short stature (present) , Decreased response to growth hormone stimulation test (present) , Myopia (present) , Abnormal optic nerve morphology (present) , … (more) Obesity (present) , Short stature (present) , Decreased response to growth hormone stimulation test (present) , Myopia (present) , Abnormal optic nerve morphology (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Autistic behavior (present) , Motor stereotypies (present) , Anxiety (present) , Short attention span (present) , Abnormality of facial musculature (present) , Abnormal muscle physiology (present) , Feeding difficulties (present) , Abnormal esophagus morphology (present) , Abnormality of the bladder (present) (less) Indication for testing: Diagnostic Age: 0-9 years Sex: female Method: Mtochondrial Genome and Nuclear Gene Panel Testing laboratory: GeneDx Date variant was reported to submitter: 2013-11-20 Testing laboratory interpretation: Uncertain significance

Comment:

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 146 of the COQ6 protein (p.Asp146Tyr). This variant is present in population databases (rs140725181, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with COQ6-related conditions. ClinVar contains an entry for this variant (Variation ID: 214235). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

Comment:

The c.436G>T (p.D146Y) alteration is located in exon 4 (coding exon 4) of the COQ6 gene. This alteration results from a G to T substitution at nucleotide position 436, causing the aspartic acid (D) at amino acid position 146 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

Variant interpreted as Uncertain significance and reported on 11-20-2013 by Lab GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs140725181 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_182476.3(COQ6):c.436G>T (p.Asp146Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs140725181 ...