NM_004168.4(SDHA):c.1753C>T (p.Arg585Trp) AND Neurodegeneration with ataxia and late-onset optic atrophy

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Sep 23, 2024
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:: RCV001824123.7

Allele description [Variation Report for NM_004168.4(SDHA):c.1753C>T (p.Arg585Trp)]

NM_004168.4(SDHA):c.1753C>T (p.Arg585Trp)

Gene:

SDHA:succinate dehydrogenase complex flavoprotein subunit A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5p15.33

Genomic location:

Preferred name:

NM_004168.4(SDHA):c.1753C>T (p.Arg585Trp)

HGVS:

NC_000005.10:g.251427C>T
NG_012339.1:g.38187C>T
NM_001294332.2:c.1609C>T
NM_001330758.2:c.1552-2966C>T
NM_004168.4:c.1753C>TMANE SELECT
NP_001281261.1:p.Arg537Trp
NP_004159.2:p.Arg585Trp
LRG_315t1:c.1753C>T
LRG_315:g.38187C>T
LRG_315p1:p.Arg585Trp
NC_000005.9:g.251542C>T
NM_004168.2:c.1753C>T
NM_004168.3:c.1753C>T
p.R585W

Protein change:

R537W; ARG585TRP

Links:

OMIM: 600857.0009; dbSNP: rs200397144

Molecular consequence:

NM_001330758.2:c.1552-2966C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001294332.2:c.1609C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004168.4:c.1753C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Neurodegeneration with ataxia and late-onset optic atrophy
Identifiers:: MONDO: MONDO:0031006; MedGen: C5543254; OMIM: 619259

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002073763	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 5, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 21752896, 23666964, 28500238, 25720320, 29177515, 30050099, 25741868
SCV005394833	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 23, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 21752896, 25720320, 28546994, 23666964, 35988656, 36593350, 35171114 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002073763

DASA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 5, 2022)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV005394833

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Sep 23, 2024)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	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

Citations

PubMed

SDHA mutated paragangliomas may be at high risk of metastasis.

Tufton N, Ghelani R, Srirangalingam U, Kumar AV, Drake WM, Iacovazzo D, Skordilis K, Berney D, Al-Mrayat M, Khoo B, Akker SA.

Endocr Relat Cancer. 2017 Jul;24(7):L43-L49. doi: 10.1530/ERC-17-0030. Epub 2017 May 12. No abstract available.

PubMed [citation]

PMID:: 28500238

Clinical Aspects of SDHA-Related Pheochromocytoma and Paraganglioma: A Nationwide Study.

van der Tuin K, Mensenkamp AR, Tops CMJ, Corssmit EPM, Dinjens WN, van de Horst-Schrivers ANA, Jansen JC, de Jong MM, Kunst HPM, Kusters B, Leter EM, Morreau H, van Nesselrooij BMP, Oldenburg RA, Spruijt L, Hes FJ, Timmers HJLM.

J Clin Endocrinol Metab. 2018 Feb 1;103(2):438-445. doi: 10.1210/jc.2017-01762. Erratum in: J Clin Endocrinol Metab. 2018 May 1;103(5):2077. doi: 10.1210/jc.2018-00533..

PubMed [citation]

PMID:: 29177515

See all PubMed Citations (11)

Details of each submission

From DASA, SCV002073763.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (7)

Description

The c.1753C>T;p.(Arg585Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 160358; PMID: 21752896; 23666964; 28500238; 25720320; 29177515; 30050099) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Succ_DH_flav_C) - PM1. The variant is present at low allele frequencies population databases (rs200397144 – gnomAD 0.00001314%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely 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		1	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005394833.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: SDHA c.1753C>T (p.Arg585Trp) results in a non-conservative amino acid change located in the fumarate reductase/succinate dehydrogenase flavoprotein-like, C-terminal domain (IPR015939) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250906 control chromosomes. c.1753C>T has been reported in the literature in the heterozygous state in multiple individuals affected with pheochromocytoma, paraganglioma, and gastrointestinal stromal tumor (Richter_2022, Korpershoek_2011, Rattenberr_2013, Jahn_2022, Mandelker_2023, Casey_2017, Papathomas_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28546994, 35988656, 21752896, 36593350, 25720320, 23666964, 35171114). ClinVar contains an entry for this variant (Variation ID: 160358). Based on the evidence outlined above, the variant was classified as pathogenic.

#	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

Last Updated: Mar 1, 2026

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