NM_174889.5(NDUFAF2):c.114C>G (p.Tyr38Ter) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 24, 2024
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:: RCV000485122.6

Allele description [Variation Report for NM_174889.5(NDUFAF2):c.114C>G (p.Tyr38Ter)]

NM_174889.5(NDUFAF2):c.114C>G (p.Tyr38Ter)

Genes:

ERCC8:ERCC excision repair 8, CSA ubiquitin ligase complex subunit [Gene - OMIM - HGNC]
NDUFAF2:NADH:ubiquinone oxidoreductase complex assembly factor 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q12.1

Genomic location:

Preferred name:

NM_174889.5(NDUFAF2):c.114C>G (p.Tyr38Ter)

HGVS:

NC_000005.10:g.60945369C>G
NG_008978.1:g.5241C>G
NG_009289.1:g.4710G>C
NM_174889.5:c.114C>GMANE SELECT
NP_777549.1:p.Tyr38Ter
LRG_466:g.4710G>C
NC_000005.9:g.60241196C>G
NM_174889.4:c.114C>G

Protein change:

Y38*; TYR38TER

Links:

Counsyl: 525402; OMIM: 609653.0004; dbSNP: rs199754807

NCBI 1000 Genomes Browser:

rs199754807

Molecular consequence:

NM_174889.5:c.114C>G - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000566903	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 26, 2023)	germline	clinical testing	Citation Link,
SCV004291832	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18180188, 19384974, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000566903

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(May 26, 2023)

germline

clinical testing

Citation Link,

SCV004291832

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 24, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The unique neuroradiology of complex I deficiency due to NDUFA12L defect.

Barghuti F, Elian K, Gomori JM, Shaag A, Edvardson S, Saada A, Elpeleg O.

Mol Genet Metab. 2008 May;94(1):78-82. doi: 10.1016/j.ymgme.2007.11.013. Epub 2008 Jan 3.

PubMed [citation]

PMID:: 18180188

Baculovirus complementation restores a novel NDUFAF2 mutation causing complex I deficiency.

Hoefs SJ, Dieteren CE, Rodenburg RJ, Naess K, Bruhn H, Wibom R, Wagena E, Willems PH, Smeitink JA, Nijtmans LG, van den Heuvel LP.

Hum Mutat. 2009 Jul;30(7):E728-36. doi: 10.1002/humu.21037.

PubMed [citation]

PMID:: 19384974

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000566903.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19384974)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004291832.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Tyr38*) in the NDUFAF2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NDUFAF2 are known to be pathogenic (PMID: 18180188). This variant is present in population databases (rs199754807, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 19384974). ClinVar contains an entry for this variant (Variation ID: 419231). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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