NM_004544.4(NDUFA10):c.712G>A (p.Glu238Lys) AND Leigh syndrome

Germline classification:: Benign/Likely benign (3 submissions)
Last evaluated:: May 28, 2019
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:: RCV000987070.7

Allele description [Variation Report for NM_004544.4(NDUFA10):c.712G>A (p.Glu238Lys)]

NM_004544.4(NDUFA10):c.712G>A (p.Glu238Lys)

Gene:

NDUFA10:NADH:ubiquinone oxidoreductase subunit A10 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q37.3

Genomic location:

Preferred name:

NM_004544.4(NDUFA10):c.712G>A (p.Glu238Lys)

Other names:

p.E238K:GAG>AAG

HGVS:

NC_000002.12:g.240011654C>T
NG_031855.2:g.18749G>A
NM_001322019.2:c.712G>A
NM_001322020.2:c.712G>A
NM_004544.4:c.712G>AMANE SELECT
NP_001308948.1:p.Glu238Lys
NP_001308949.1:p.Glu238Lys
NP_004535.1:p.Glu238Lys
NC_000002.11:g.240951071C>T
NM_004544.3:c.712G>A
NR_136155.2:n.3795G>A
NR_136156.2:n.3795G>A
NR_136157.2:n.3626G>A
NR_136158.2:n.3795G>A

Protein change:

E238K

Links:

dbSNP: rs35462421

NCBI 1000 Genomes Browser:

rs35462421

Molecular consequence:

NM_001322019.2:c.712G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322020.2:c.712G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004544.4:c.712G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_136155.2:n.3795G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_136156.2:n.3795G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_136157.2:n.3626G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_136158.2:n.3795G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Leigh syndrome (NULS)
Synonyms:: Leigh Disease; Subacute necrotizing encephalopathy; Necrotizing encephalopathy infantile subacute of Leigh; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009723; MedGen: C2931891; Orphanet: 506; OMIM: 256000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001136263	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Likely benign (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001298102	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Benign (Apr 27, 2017)	germline	clinical testing	Citation Link,
SCV001549010	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Benign	unknown	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001136263

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Likely benign
(May 28, 2019)

unknown

clinical testing

Citation Link,

SCV001298102

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Benign
(Apr 27, 2017)

germline

clinical testing

Citation Link,

SCV001549010

Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided

Benign

unknown

clinical testing

Help

Summary from all submissions

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

Details of each submission

From Mendelics, SCV001136263.1

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

#	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

From Illumina Laboratory Services, Illumina, SCV001298102.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

#	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

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001549010.1

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

Description

The NDUFA10 p.E238K variant was not identified in the literature but was identified in dbSNP (ID: rs35462421) and ClinVar (classified as likely benign by Invitae and three other laboratories; and as benign by GeneDx and Illumina). The variant was identified in control databases in 1601 of 282886 chromosomes (7 homozygous) at a frequency of 0.005660, and was observed at the highest frequency in the European (non-Finnish) population in 1009 of 129192 chromosomes (5 homozygous) (freq: 0.007810) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.E238 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however this is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

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

Last Updated: Nov 24, 2024

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