VCV000138437.34 - ClinVar

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

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.

(10)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 138437 Accession: VCV000138437.34

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q37.3 2: 240011654 (GRCh38) [ NCBI UCSC ] 2: 240951071 (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	Jun 23, 2014	Oct 20, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004544.4:c.712G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004535.1:p.Glu238Lys	missense
NM_001322019.2:c.712G>A	NP_001308948.1:p.Glu238Lys	missense
NM_001322020.2:c.712G>A	NP_001308949.1:p.Glu238Lys	missense
NR_136155.2:n.3795G>A		non-coding transcript variant
NR_136156.2:n.3795G>A		non-coding transcript variant
NR_136157.2:n.3626G>A		non-coding transcript variant
NR_136158.2:n.3795G>A		non-coding transcript variant
NC_000002.12:g.240011654C>T
NC_000002.11:g.240951071C>T
NG_031855.2:g.18749G>A

... more HGVS ... less HGVS

Protein change

E238K

Other names

p.E238K:GAG>AAG

Canonical SPDI

NC_000002.12:240011653:C:T

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.

0.00280 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00280

1000 Genomes Project 30x 0.00297

Exome Aggregation Consortium (ExAC) 0.00536

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00538

The Genome Aggregation Database (gnomAD) 0.00570

Trans-Omics for Precision Medicine (TOPMed) 0.00639

The Genome Aggregation Database (gnomAD), exomes 0.00579

Links

ClinGen: CA292421 dbSNP: rs35462421 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.
NDUFA10		-	-	GRCh38 GRCh38 GRCh37	352	452

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.
not specified	Benign (1)	criteria provided, single submitter	Apr 7, 2014	RCV000127101.2
not provided	Likely benign (4)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000514175.26
Leigh syndrome	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	May 28, 2019	RCV000987070.7
Mitochondrial complex I deficiency, nuclear type 1	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV001138077.5
Mitochondrial complex 1 deficiency, nuclear type 22	Likely benign (1)	criteria provided, single submitter	Feb 7, 2022	RCV002492481.2

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.
Benign (Apr 07, 2014)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000170655.12 First in ClinVar: Jun 23, 2014 Last updated: Jun 23, 2014	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Likely benign (Jan 29, 2024)	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: SCV001113439.5 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005261897.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Leigh syndrome Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001136263.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Leigh syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001298102.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: 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, … (more) 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. (less)
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Mitochondrial complex I deficiency, nuclear type 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001298103.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: 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, … (more) 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002544236.16 First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024	Comment: NDUFA10: BS2 Number of individuals with the variant: 11
Likely benign (May 11, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000610540.1 First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017
Likely benign (Feb 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitochondrial complex 1 deficiency, nuclear type 22 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002800574.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (-)	no assertion criteria provided Method: clinical testing	Leigh syndrome Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001549010.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: 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 … (more) 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. (less)

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

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.

Comment:

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

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.

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:

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs35462421 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs35462421 ...