VCV000694327.13 - ClinVar

NM_004168.4(SDHA):c.1984C>T (p.Arg662Cys)

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.

(4)

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
Likely pathogenic(1); Uncertain significance(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004168.4(SDHA):c.1984C>T (p.Arg662Cys)

Variation ID: 694327 Accession: VCV000694327.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5p15.33 5: 256409 (GRCh38) [ NCBI UCSC ] 5: 256524 (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	Apr 24, 2020	May 1, 2024	Mar 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004168.4:c.1984C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004159.2:p.Arg662Cys	missense
NM_001294332.2:c.1840C>T	NP_001281261.1:p.Arg614Cys	missense
NM_001330758.2:c.1741C>T	NP_001317687.1:p.Arg581Cys	missense
NM_004168.2:c.1984C>T
NC_000005.10:g.256409C>T
NC_000005.9:g.256524C>T
NG_012339.1:g.43169C>T
LRG_315:g.43169C>T
LRG_315t1:c.1984C>T	LRG_315p1:p.Arg662Cys

... more HGVS ... less HGVS

Protein change

R581C, R614C, R662C

Other names

Canonical SPDI

NC_000005.10:256408:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

variation affecting protein; Variation Ontology [ VariO:0002]

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.

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

Links

dbSNP: rs1737195067 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.
SDHA		-	-	GRCh38 GRCh37	2735	2894

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.
Mitochondrial complex II deficiency, nuclear type 1	Likely pathogenic (1)	criteria provided, single submitter	Sep 25, 2019	RCV001078147.1
Mitochondrial complex II deficiency, nuclear type 1 Paragangliomas 5	Uncertain significance (1)	criteria provided, single submitter	Mar 23, 2023	RCV001224277.8
not provided	Uncertain significance (1)	criteria provided, single submitter	Nov 30, 2022	RCV001759641.2
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Apr 9, 2020	RCV002415972.2

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.
Likely pathogenic (Sep 25, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitochondrial complex II deficiency, nuclear type 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Clinical Genetics Laboratory, Emek Medical Center Accession: SCV000996311.1 First in ClinVar: Apr 24, 2020 Last updated: Apr 24, 2020	Comment: The p.Arg662Cys in SDHA gene was found in affected girl with bilateral optic atrophy, global developmental delay and intellectual disability. This is a very rare … (more) The p.Arg662Cys in SDHA gene was found in affected girl with bilateral optic atrophy, global developmental delay and intellectual disability. This is a very rare variant absent from databases such as GnomAD and ExAC and is de novo. Another heterozygous variant p.Arg451Cys was described previously in 5 affected individuals with optic atrophy and neurological abnormalities (Courage et al 2017, Birch-Machin et al 2000). Biochemical studies showed decreased (40-50% of control) SDH and mitochondrial respiratory chain Complex II deficiency in patient derived fibroblasts and lymphocytes. Based on the above (proper clinical features resembling previous reports, absence of variant from controls and evidence of appropriate biochemical studies e.g decreased enzyme activity we consider p.Arg662Cys pathogenic and the cause for our patient's clinical features. (less) Clinical Features: Optic atrophy (present) , Moderate global developmental delay (present) , Global developmental delay (present) Indication for testing: clinical features observed in the individual Age: 10-19 years Sex: female Ethnicity/Population group: Arab Geographic origin: Israel Comment on evidence: The variant is rare and highly evolutionary preserved. There is also biochemical support of pathogenecity.
Uncertain significance (Nov 30, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002007367.2 First in ClinVar: Nov 06, 2021 Last updated: Dec 11, 2022	Comment: De novo variant with confirmed parentage in a patient with features of a neurodevelopmental phenotype and ataxia tested at GeneDx and in an unrelated patient … (more) De novo variant with confirmed parentage in a patient with features of a neurodevelopmental phenotype and ataxia tested at GeneDx and in an unrelated patient in published literature with developmental delay, intellectual disability, nystagmus, and bilateral optic atrophy with decrease in visual acuity (Zehavi et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33471299) (less)
Uncertain significance (Mar 23, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Paragangliomas 5 Mitochondrial complex II deficiency, nuclear type 1 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001396465.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024	Comment: 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 … (more) 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SDHA protein function. ClinVar contains an entry for this variant (Variation ID: 694327). This variant has not been reported in the literature in individuals affected with SDHA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 662 of the SDHA protein (p.Arg662Cys). (less)
Uncertain significance (Apr 09, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002719063.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The p.R662C variant (also known as c.1984C>T), located in coding exon 15 of the SDHA gene, results from a C to T substitution at nucleotide … (more) The p.R662C variant (also known as c.1984C>T), located in coding exon 15 of the SDHA gene, results from a C to T substitution at nucleotide position 1984. The arginine at codon 662 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

The p.Arg662Cys in SDHA gene was found in affected girl with bilateral optic atrophy, global developmental delay and intellectual disability. This is a very rare variant absent from databases such as GnomAD and ExAC and is de novo. Another heterozygous variant p.Arg451Cys was described previously in 5 affected individuals with optic atrophy and neurological abnormalities (Courage et al 2017, Birch-Machin et al 2000). Biochemical studies showed decreased (40-50% of control) SDH and mitochondrial respiratory chain Complex II deficiency in patient derived fibroblasts and lymphocytes. Based on the above (proper clinical features resembling previous reports, absence of variant from controls and evidence of appropriate biochemical studies e.g decreased enzyme activity we consider p.Arg662Cys pathogenic and the cause for our patient's clinical features.

Comment:

De novo variant with confirmed parentage in a patient with features of a neurodevelopmental phenotype and ataxia tested at GeneDx and in an unrelated patient in published literature with developmental delay, intellectual disability, nystagmus, and bilateral optic atrophy with decrease in visual acuity (Zehavi et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33471299)

Comment:

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SDHA protein function. ClinVar contains an entry for this variant (Variation ID: 694327). This variant has not been reported in the literature in individuals affected with SDHA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 662 of the SDHA protein (p.Arg662Cys).

Comment:

The p.R662C variant (also known as c.1984C>T), located in coding exon 15 of the SDHA gene, results from a C to T substitution at nucleotide position 1984. The arginine at codon 662 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
variation affecting protein			Clinical Genetics Laboratory, Emek Medical Center Accession: SCV000996311.1

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 rs1737195067 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_004168.4(SDHA):c.1984C>T (p.Arg662Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1737195067 ...