VCV000632170.8 - ClinVar

NM_007103.4(NDUFV1):c.753_756del (p.Pro252fs)

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.

(3)

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(2); 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_007103.4(NDUFV1):c.753_756del (p.Pro252fs)

Variation ID: 632170 Accession: VCV000632170.8

Type and length

Deletion, 4 bp

Location

Cytogenetic: 11q13.2 11: 67611046-67611049 (GRCh38) [ NCBI UCSC ] 11: 67378517-67378520 (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	May 27, 2019	Apr 20, 2024	Nov 5, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_007103.4:c.753_756del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_009034.2:p.Pro252fs	frameshift
NM_001166102.2:c.726_729del	NP_001159574.1:p.Pro243fs	frameshift
NC_000011.10:g.67611047_67611050del
NC_000011.9:g.67378518_67378521del
NG_013353.1:g.9196_9199del

... more HGVS ... less HGVS

Protein change

P252fs, P243fs

Other names

Canonical SPDI

NC_000011.10:67611045:CCCCC:C

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.

Links

dbSNP: rs1229474296 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.
NDUFV1		-	-	GRCh38 GRCh37	352	502

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.
NDUFV1-related disorder	Uncertain significance (1)	criteria provided, single submitter	Oct 19, 2018	RCV000779076.4
not provided	Pathogenic (1)	criteria provided, single submitter	Nov 5, 2023	RCV001856166.4
Leigh syndrome	Pathogenic (1)	criteria provided, single submitter	Apr 1, 2015	RCV004017737.2

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.
Uncertain significance (Oct 19, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	NDUFV1-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000915547.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (1) PubMed: 23266820 Comment: The NDUFV1 c.753_756delCCCC (p.Pro252GlnfsTer44) variant is a frameshift variant that is predicted to cause premature truncation of the protein. The variant has been reported in … (more) The NDUFV1 c.753_756delCCCC (p.Pro252GlnfsTer44) variant is a frameshift variant that is predicted to cause premature truncation of the protein. The variant has been reported in a compound heterozygous state with a second missense variant in one individual affected with Leigh syndrome (Marin et al. 2013). Control data are unavailable for this variant which is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database but this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Based on the evidence and the potential impact of frameshift variants, the p.Pro252GlnfsTer44 variant is classified as a variant of unknown significance but suspicious for pathogenicity for NDUFV1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Nov 05, 2023)	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: SCV002211789.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 10080174‚ 11349233‚ 23266820 Comment: This sequence change creates a premature translational stop signal (p.Pro252Glnfs44) in the NDUFV1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Pro252Glnfs44) in the NDUFV1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NDUFV1 are known to be pathogenic (PMID: 10080174, 11349233). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Leigh syndrome (PMID: 23266820). ClinVar contains an entry for this variant (Variation ID: 632170). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 01, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leigh syndrome (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004847945.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Publications: PubMed (1) PubMed: 23266820 Comment: The p.Pro252fs variant in NDUFV1 has been reported in 1 compound heterozygous Caucasian child with Leigh syndrome (Marin 2013) and was absent from large population … (more) The p.Pro252fs variant in NDUFV1 has been reported in 1 compound heterozygous Caucasian child with Leigh syndrome (Marin 2013) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 252 and leads to a premature termination codon 44 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Complete loss of NDUFV1 function is an established disease mechanism in Leigh syndrome. In summary, the p.Pro252fs variant meets our criteria to be classified as pathogenic for Leigh syndrome in an autosomal recessive manner (http://pcpgmwww.partners.org/personalizedmedicince/LMM) based upon absence from controls and the predicted impact to the protein. (less)

Comment:

The NDUFV1 c.753_756delCCCC (p.Pro252GlnfsTer44) variant is a frameshift variant that is predicted to cause premature truncation of the protein. The variant has been reported in a compound heterozygous state with a second missense variant in one individual affected with Leigh syndrome (Marin et al. 2013). Control data are unavailable for this variant which is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database but this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Based on the evidence and the potential impact of frameshift variants, the p.Pro252GlnfsTer44 variant is classified as a variant of unknown significance but suspicious for pathogenicity for NDUFV1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

This sequence change creates a premature translational stop signal (p.Pro252Glnfs*44) in the NDUFV1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NDUFV1 are known to be pathogenic (PMID: 10080174, 11349233). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Leigh syndrome (PMID: 23266820). ClinVar contains an entry for this variant (Variation ID: 632170). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.Pro252fs variant in NDUFV1 has been reported in 1 compound heterozygous Caucasian child with Leigh syndrome (Marin 2013) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 252 and leads to a premature termination codon 44 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Complete loss of NDUFV1 function is an established disease mechanism in Leigh syndrome. In summary, the p.Pro252fs variant meets our criteria to be classified as pathogenic for Leigh syndrome in an autosomal recessive manner (http://pcpgmwww.partners.org/personalizedmedicince/LMM) based upon absence from controls and the predicted impact to the protein.

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
Leigh syndrome associated with mitochondrial complex I deficiency due to novel mutations In NDUFV1 and NDUFS2.	Marin SE	Gene	2013	PMID: 23266820
Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency.	Bénit P	American journal of human genetics	2001	PMID: 11349233
Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy.	Schuelke M	Nature genetics	1999	PMID: 10080174

Text-mined citations for rs1229474296 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_007103.4(NDUFV1):c.753_756del (p.Pro252fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1229474296 ...