NM_002495.4(NDUFS4):c.316C>T (p.Arg106Ter) AND Mitochondrial complex I deficiency, nuclear type 1

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Dec 20, 2023
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:: RCV000735424.4

Allele description [Variation Report for NM_002495.4(NDUFS4):c.316C>T (p.Arg106Ter)]

NM_002495.4(NDUFS4):c.316C>T (p.Arg106Ter)

Gene:

NDUFS4:NADH:ubiquinone oxidoreductase subunit S4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q11.2

Genomic location:

Preferred name:

NM_002495.4(NDUFS4):c.316C>T (p.Arg106Ter)

HGVS:

NC_000005.10:g.53646371C>T
NG_008200.1:g.90737C>T
NM_001318051.2:c.316C>T
NM_002495.4:c.316C>TMANE SELECT
NP_001304980.1:p.Arg106Ter
NP_002486.1:p.Arg106Ter
NC_000005.9:g.52942201C>T
NM_002495.2:c.316C>T
NM_002495.3:c.316C>T
NR_134473.2:n.512C>T
NR_134474.2:n.429C>T
NR_134475.2:n.464C>T

Protein change:

R106*; ARG106TER

Links:

OMIM: 602694.0003; dbSNP: rs104893898

NCBI 1000 Genomes Browser:

rs104893898

Molecular consequence:

NR_134473.2:n.512C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_134474.2:n.429C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_134475.2:n.464C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001318051.2:c.316C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_002495.4:c.316C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Mitochondrial complex I deficiency, nuclear type 1
Synonyms:: NADH-COENZYME Q REDUCTASE DEFICIENCY; MITOCHONDRIAL NADH DEHYDROGENASE COMPONENT OF COMPLEX I, DEFICIENCY OF
Identifiers:: MONDO: MONDO:0100224; MedGen: CN257533; OMIM: 252010

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000027488	OMIM	no assertion criteria provided	Pathogenic (Aug 18, 2000)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001426440	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004046168	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005056237	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 20, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

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

Citations

PubMed

Combined enzymatic complex I and III deficiency associated with mutations in the nuclear encoded NDUFS4 gene.

Budde SM, van den Heuvel LP, Janssen AJ, Smeets RJ, Buskens CA, DeMeirleir L, Van Coster R, Baethmann M, Voit T, Trijbels JM, Smeitink JA.

Biochem Biophys Res Commun. 2000 Aug 18;275(1):63-8.

PubMed [citation]

PMID:: 10944442

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000027488.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a patient with complex I deficiency and decreased complex III activity, Budde et al. (2000) identified a 316C-T transition of the NDUFS4 cDNA, causing an arg106-to-stop amino acid change. The patient was homozygous for the mutation; his parents, who were consanguineous, and a brother were heterozygous. Except for hypospadias noted at birth, the patient appeared normal until the age of 7 weeks at which time muscular hypotonia and lack of visual and auditive attention were observed. At the age of 3 months he was found to have elevated lactate levels in the blood. Cranial MRI showed hyperintense signals resembling those found in Leigh syndrome (256000). Cardiac ultrasound showed concentric hypertrophy of the left ventricle with hypercontractility. He died from cardiocirculatory insufficiency.

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

From Centogene AG - the Rare Disease Company, SCV001426440.1

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

#	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 Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV004046168.1

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

Description

This nonsense variant found in exon 3 of 5 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a homozygous change in patients with mitochondrial complex I deficiency (PMID: 10944442). Functional studies have shown the presence of this variant results in a reduction of complex I enzymatic activity in skeletal muscle (PMID: 10944442). The c.316C>T (p.Arg106Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004 % (1/251396) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.316C>T (p.Arg106Ter) variant is classified as Pathogenic.

#	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 Baylor Genetics, SCV005056237.1

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

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

Last Updated: Sep 29, 2024

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