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NM_005006.7(NDUFS1):c.1393-2A>C AND not provided

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Nov 15, 2022
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000197167.11

Allele description [Variation Report for NM_005006.7(NDUFS1):c.1393-2A>C]

NM_005006.7(NDUFS1):c.1393-2A>C

Gene:
NDUFS1:NADH:ubiquinone oxidoreductase core subunit S1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q33.3
Genomic location:
Preferred name:
NM_005006.7(NDUFS1):c.1393-2A>C
HGVS:
  • NC_000002.12:g.206133107T>G
  • NG_009248.1:g.31357A>C
  • NG_009248.2:g.31337A>C
  • NM_001199981.2:c.1285-2A>C
  • NM_001199982.2:c.1060-2A>C
  • NM_001199983.2:c.1222-2A>C
  • NM_001199984.2:c.1435-2A>C
  • NM_005006.7:c.1393-2A>CMANE SELECT
  • NC_000002.11:g.206997831T>G
  • NM_005006.5:c.1393-2A>C
Links:
dbSNP: rs370009373
NCBI 1000 Genomes Browser:
rs370009373
Molecular consequence:
  • NM_001199981.2:c.1285-2A>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001199982.2:c.1060-2A>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001199983.2:c.1222-2A>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001199984.2:c.1435-2A>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_005006.7:c.1393-2A>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000251854GeneDx
criteria provided, single submitter

(GeneDx Variant Classification (06012015))		Pathogenic
(Jun 12, 2014) 		germlineclinical testing

Citation Link,

SCV002953821Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Nov 15, 2022) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]
PMID:
16199547
PMCID:
PMC1735933

Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency.

Bénit P, Chretien D, Kadhom N, de Lonlay-Debeney P, Cormier-Daire V, Cabral A, Peudenier S, Rustin P, Munnich A, Rötig A.

Am J Hum Genet. 2001 Jun;68(6):1344-52. Epub 2001 May 7.

PubMed [citation]
PMID:
11349233
PMCID:
PMC1226121
See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000251854.11

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

c.1393-2 A>C: IVS13-2 A>C in intron 13 of the NDUFS1 gene (NM_005006.5). The c.1393-2 A>C splice site mutation in the NDUFS1 gene destroys the canonical splice acceptor site in intron 13. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Although this mutation has not been previously reported to our knowledge, it is expected to be pathogenic. The variant is found in MITONUC-MITOP panel(s).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV002953821.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 214772). This variant has not been reported in the literature in individuals affected with NDUFS1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects an acceptor splice site in intron 13 of the NDUFS1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NDUFS1 are known to be pathogenic (PMID: 11349233, 22200994).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 15, 2024