VCV002581720.1 - ClinVar

NM_001370595.2(COA8):c.170_173dup (p.Pro59fs)

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.

(1)

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.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001370595.2(COA8):c.170_173dup (p.Pro59fs)

Variation ID: 2581720 Accession: VCV002581720.1

Type and length

Duplication, 4 bp

Location

Cytogenetic: 14q32.33 14: 103571668-103571669 (GRCh38) [ NCBI UCSC ] 14: 104038005-104038006 (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 7, 2023	Oct 7, 2023	Sep 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001370595.2:c.170_173dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001357524.1:p.Pro59fs	frameshift
NM_001370595.2:c.170_173dupGACC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		frameshift
NM_001302653.2:c.170_173dup	NP_001289582.2:p.Pro59fs	frameshift
NM_001302654.2:c.170_173dup	NP_001289583.2:p.Pro59fs	frameshift
NM_032374.4:c.209_212dup	NP_115750.2:p.Pro72Thrfs	frameshift
NR_126431.2:n.377_380dup		non-coding transcript variant
NR_126432.2:n.212_215dup		non-coding transcript variant
NC_000014.9:g.103571669_103571672dup
NC_000014.8:g.104038006_104038009dup
NG_041786.1:g.13713_13716dup

... more HGVS ... less HGVS

Protein change

P59fs

Other names

Canonical SPDI

NC_000014.9:103571668:GACC:GACCGACC

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

effect on protein activity; Variation Ontology [ VariO:0053]

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.

Links

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.
COA8		-	-	GRCh38 GRCh37	161	225

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.
Mitochondrial complex 4 deficiency, nuclear type 17	Pathogenic (1)	criteria provided, single submitter	Sep 27, 2023	RCV003332426.2

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.
Pathogenic (Sep 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing, in vitro	Mitochondrial complex 4 deficiency, nuclear type 17 (Autosomal recessive inheritance) Affected status: not applicable, yes Allele origin: germline, not applicable	Department of Pathophysiology and Transplantation, University of Milan Accession: SCV004036156.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023	Comment: The variant was found in two Italian siblings presenting a mitochondrial encephalomyopathy. Patient 1 is a 51-year-old woman who presented generalized epilepsy and retinitis pigmentosa … (more) The variant was found in two Italian siblings presenting a mitochondrial encephalomyopathy. Patient 1 is a 51-year-old woman who presented generalized epilepsy and retinitis pigmentosa at 10 years of age followed by hearing loss. Neurological examination shows bilateral ptosis, muscle weakness, cramps and myalgia after exercise, peripheral neuropathy, mild dysarthria and dysphonia, cognitive impairment. Muscle biopsy had showed signs of mitochondrial dysfunction. Patient 2 (Patient 1’s sister) is a 50-year-old woman presenting fatigability, myalgia, and hearing loss. Neurological examination showed ptosis and muscle weakness. Muscle biopsy displayed a diffuse reduction of COX activity staining and ragged-red fibers. Both sisters presented secondary amenorrhea. The variant was confirmed at cDNA level and biochemical analysis showed a detrimental effect on Respiratory Chain Complex IV (COX) activity and stability. (less) Observation 1: Clinical Features: Autosomal recessive inheritance (present) , Cytochrome C oxidase-negative muscle fibers (present) , Bilateral ptosis (present) , Dysphagia (present) , Limb muscle weakness (present) Zygosity: Homozygote Age: 50-59 years Sex: female Ethnicity/Population group: Caucasian Geographic origin: Italy Observation 2: Clinical Features: Limb muscle weakness (present) , Autosomal recessive inheritance (present) , Cytochrome C oxidase-negative muscle fibers (present) Zygosity: Homozygote Age: 50-59 years Sex: female Ethnicity/Population group: Caucasian Geographic origin: Italy Observation 3: Sex: female Tissue: Skeletal muscle Result: Biochemical assay revealed marked increase of citrate synthetase (CS) activity in muscle homogenate (patient: 329.2 pmol/min/mg; controls: 137.3 ± 15.0 pmol/min/mg), resulting in reduced values of all the respiratory chain activities when normalized to CS. COX activity normalized to CS showed the most severe defect in muscle (<5% of the controls’ mean). Observation 4: Sex: female Tissue: Skeletal muscle Result: By protein analyses, we identiﬁed profound deﬁciency of subunits COX-II, COX-III, COX-IV and, to a lesser extent, of COX-I which are integral to the assembly of complex IV.

Comment:

The variant was found in two Italian siblings presenting a mitochondrial encephalomyopathy. Patient 1 is a 51-year-old woman who presented generalized epilepsy and retinitis pigmentosa at 10 years of age followed by hearing loss. Neurological examination shows bilateral ptosis, muscle weakness, cramps and myalgia after exercise, peripheral neuropathy, mild dysarthria and dysphonia, cognitive impairment. Muscle biopsy had showed signs of mitochondrial dysfunction. Patient 2 (Patient 1’s sister) is a 50-year-old woman presenting fatigability, myalgia, and hearing loss. Neurological examination showed ptosis and muscle weakness. Muscle biopsy displayed a diffuse reduction of COX activity staining and ragged-red fibers. Both sisters presented secondary amenorrhea. The variant was confirmed at cDNA level and biochemical analysis showed a detrimental effect on Respiratory Chain Complex IV (COX) activity and stability.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
effect on protein activity (VariO:0053)	Method not provided Method not provided	Biochemical assay revealed marked increase of citrate synthetase (CS) activity in muscle homogenate (patient: 329.2 pmol/min/mg; controls: 137.3 ± 15.0 pmol/min/mg), resulting in reduced values of all the respiratory chain activities when normalized to CS. COX activity normalized to CS showed the most severe defect in muscle (<5% of the controls’ mean). By protein analyses, we identiﬁed profound deﬁciency of subunits COX-II, COX-III, COX-IV and, to a lesser extent, of COX-I which are integral to the assembly of complex IV.	Department of Pathophysiology and Transplantation, University of Milan Accession: SCV004036156.1

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 this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_001370595.2(COA8):c.170_173dup (p.Pro59fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...