ClinVar Genomic variation as it relates to human health
NM_021074.5(NDUFV2):c.669_670insG (p.Ser224fs)
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.
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(1); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_021074.5(NDUFV2):c.669_670insG (p.Ser224fs)
Variation ID: 617494 Accession: VCV000617494.6
- Type and length
-
Insertion, 1 bp
- Location
-
Cytogenetic: 18p11.22 18: 9134198-9134199 (GRCh38) [ NCBI UCSC ] 18: 9134196-9134197 (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 Jan 31, 2019 Feb 14, 2024 Mar 24, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_021074.5:c.669_670insG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066552.2:p.Ser224fs frameshift NM_021074.3:c.669_670insG NM_021074.4:c.669_670insG NC_000018.10:g.9134198_9134199insG NC_000018.9:g.9134196_9134197insG NG_013355.1:g.36569_36570insG NG_047134.1:g.2446_2447insG - Protein change
- S224fs
- Other names
- -
- Canonical SPDI
- NC_000018.10:9134198::G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe 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) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00004
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 | ||
---|---|---|---|---|---|---|
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. |
|||
NDUFV2 | - | - |
GRCh38 GRCh37 |
42 | 242 | |
NDUFV2-AS1 | - | - | - | GRCh38 | - | 121 |
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. |
---|---|---|---|---|
Uncertain significance (2) |
criteria provided, single submitter
|
Oct 19, 2020 | RCV000754626.3 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Mar 24, 2023 | RCV002533771.3 |
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 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial complex 1 deficiency, nuclear type 7
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767781.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3A-VUS. Following criteria are met: 0102 - Loss of function is a likely mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3A-VUS. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with mitochondrial complex I deficiency, nuclear type 7 (MIM#618229). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. While it is hypothesised that transcripts containing this variant were still subjected to nonsense-mediated decay (NMD), data was not shown in the manuscript for independent assessment (PMID: 26008862). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 9 heterozygotes, 0 homozygotes). (SP) 0402 - Variant is located in a gene associated with a severe early-onset recessive condition that is intolerant to bi-allelic loss of function variants (gnomAD, OMIM). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable downstream truncating variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. A pair of siblings with hypertrophic cardiomyopathy and encephalopathy were compound heterozygotes for this variant and a splice site variant (PMID: 26008862). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
Pathogenic
(Mar 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004036679.1
First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect, including dramatically decreased protein level and absence of transcripts containing this variant, indicative of nonsense mediated decay (Cameron et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26008862) (less)
|
|
Uncertain significance
(Jul 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV003278958.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 617494). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 26008862). This variant is present in population databases (rs772188600, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Ser224Valfs*3) in the NDUFV2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acid(s) of the NDUFV2 protein. (less)
|
|
Pathogenic
(Jan 25, 2019)
|
no assertion criteria provided
Method: literature only
|
MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 7
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000882546.1
First in ClinVar: Jan 31, 2019 Last updated: Jan 31, 2019 |
Comment on evidence:
For discussion of the 1-bp insertion (c.669_670insG) in the NDUFV2 gene, resulting in a frameshift and premature termination (Ser224ValfsTer3), that was found in compound heterozygous … (more)
For discussion of the 1-bp insertion (c.669_670insG) in the NDUFV2 gene, resulting in a frameshift and premature termination (Ser224ValfsTer3), that was found in compound heterozygous state in 2 sibs with isolated complex I deficiency nuclear type 7 (MC1DN7; 618229) by Cameron et al. (2015), see 600532.0002. (less)
|
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Exome sequencing identifies complex I NDUFV2 mutations as a novel cause of Leigh syndrome. | Cameron JM | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2015 | PMID: 26008862 |
Text-mined citations for rs772188600 ...
HelpRecord last updated Feb 14, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.