VCV000214795.50 - ClinVar

NM_001377299.1(NDUFS2):c.1138C>G (p.His380Asp)

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.

(9)

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.

Conflicting classifications of pathogenicity
Uncertain significance(8); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001377299.1(NDUFS2):c.1138C>G (p.His380Asp)

Variation ID: 214795 Accession: VCV000214795.50

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q23.3 1: 161213401 (GRCh38) [ NCBI UCSC ] 1: 161183191 (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	Dec 19, 2017	Nov 24, 2024	Sep 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001377299.1:c.1138C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001364228.1:p.His380Asp	missense
NM_001166159.2:c.1138C>G	NP_001159631.1:p.His380Asp	missense
NM_001377298.1:c.1138C>G	NP_001364227.1:p.His380Asp	missense
NM_001377300.1:c.1138C>G	NP_001364229.1:p.His380Asp	missense
NM_001377301.1:c.1138C>G	NP_001364230.1:p.His380Asp	missense
NM_001377302.1:c.1138C>G	NP_001364231.1:p.His380Asp	missense
NM_004550.5:c.1138C>G	NP_004541.1:p.His380Asp	missense
NR_165188.1:n.1027C>G		non-coding transcript variant
NC_000001.11:g.161213401C>G
NC_000001.10:g.161183191C>G
NG_013352.1:g.19087C>G
NG_029043.1:g.3105C>G

... more HGVS ... less HGVS

Protein change

H380D

Other names

p.H380D:CAT>GAT
p.His380Asp

Canonical SPDI

NC_000001.11:161213400:C:G

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.

0.00020 (G)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00123

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

The Genome Aggregation Database (gnomAD), exomes 0.00042

Trans-Omics for Precision Medicine (TOPMed) 0.00051

The Genome Aggregation Database (gnomAD) 0.00055

Exome Aggregation Consortium (ExAC) 0.00064

Links

ClinGen: CA321716 dbSNP: rs144411579 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.
NDUFS2		-	-	GRCh38 GRCh37	206	270

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 provided	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Sep 27, 2023	RCV000725777.36
Mitochondrial complex 1 deficiency, nuclear type 6	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 8, 2022	RCV001001527.11
Mitochondrial complex I deficiency, nuclear type 1	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001100725.5
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Aug 4, 2021	RCV002515415.3

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.
Uncertain significance (Feb 16, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000339314.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NDUFS2 Number of individuals with the variant: 1 Sex: mixed
Uncertain significance (Apr 05, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000251877.15 First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023	Comment: Identified in the single heterozygous state without a second NDUFS2 variant in an individual with a FARSB-related disorder in the published literature, and suggested to … (more) Identified in the single heterozygous state without a second NDUFS2 variant in an individual with a FARSB-related disorder in the published literature, and suggested to be unrelated to the individual's phenotype (Antonellis et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29573043) (less)
Uncertain significance (Feb 21, 2019)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	Mitochondrial complex 1 deficiency, nuclear type 6 Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001158839.1 First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020	Comment: The NDUFS2 c.1138C>G; p.His380Asp variant (rs144411579), is reported in the literature in a large sequencing study (Bastarache 2018), but has not been reported to be … (more) The NDUFS2 c.1138C>G; p.His380Asp variant (rs144411579), is reported in the literature in a large sequencing study (Bastarache 2018), but has not been reported to be associated with disease. This variant is reported as uncertain significance by multiple laboratories in ClinVar (Variation ID: 214795), and is found in the non-Finnish European population with an overall allele frequency of 0.09% (108/123,964 alleles) in the Genome Aggregation Database. The histidine at codon 380 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.His380Asp variant is uncertain at this time. References: Bastarache L et al. Phenotype risk scores identify patients with unrecognized Mendelian disease patterns. Science. 2018 Mar 16;359(6381):1233-1239. (less)
Uncertain significance (Jan 13, 2018)	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: SCV001257257.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Aug 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitochondrial complex 1 deficiency, nuclear type 6 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581129.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PM2_SUP, PP3	Number of individuals with the variant: 1 Sex: male
Uncertain significance (Oct 18, 2022)	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: SCV002129590.2 First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023	Comment: This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 380 of the NDUFS2 protein … (more) This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 380 of the NDUFS2 protein (p.His380Asp). This variant is present in population databases (rs144411579, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NDUFS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 214795). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Aug 04, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003572426.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Comment: The c.1138C>G (p.H380D) alteration is located in exon 12 (coding exon 11) of the NDUFS2 gene. This alteration results from a C to G substitution … (more) The c.1138C>G (p.H380D) alteration is located in exon 12 (coding exon 11) of the NDUFS2 gene. This alteration results from a C to G substitution at nucleotide position 1138, causing the histidine (H) at amino acid position 380 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Likely benign (Dec 01, 2022)	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: SCV000891862.28 First in ClinVar: Mar 31, 2019 Last updated: Oct 20, 2024	Comment: NDUFS2: PP3, BS1 Number of individuals with the variant: 4
Uncertain significance (Sep 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005408447.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (1) PubMed: 29573043 Comment: PP3 Number of individuals with the variant: 1

Comment:

Identified in the single heterozygous state without a second NDUFS2 variant in an individual with a FARSB-related disorder in the published literature, and suggested to be unrelated to the individual's phenotype (Antonellis et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29573043)

Comment:

The NDUFS2 c.1138C>G; p.His380Asp variant (rs144411579), is reported in the literature in a large sequencing study (Bastarache 2018), but has not been reported to be associated with disease. This variant is reported as uncertain significance by multiple laboratories in ClinVar (Variation ID: 214795), and is found in the non-Finnish European population with an overall allele frequency of 0.09% (108/123,964 alleles) in the Genome Aggregation Database. The histidine at codon 380 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.His380Asp variant is uncertain at this time. References: Bastarache L et al. Phenotype risk scores identify patients with unrecognized Mendelian disease patterns. Science. 2018 Mar 16;359(6381):1233-1239.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 380 of the NDUFS2 protein (p.His380Asp). This variant is present in population databases (rs144411579, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NDUFS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 214795). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The c.1138C>G (p.H380D) alteration is located in exon 12 (coding exon 11) of the NDUFS2 gene. This alteration results from a C to G substitution at nucleotide position 1138, causing the histidine (H) at amino acid position 380 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Compound heterozygosity for loss-of-function FARSB variants in a patient with classic features of recessive aminoacyl-tRNA synthetase-related disease.	Antonellis A	Human mutation	2018	PMID: 29573043
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NDUFS2	-	-	-	-

Text-mined citations for rs144411579 ...

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_001377299.1(NDUFS2):c.1138C>G (p.His380Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs144411579 ...