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

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 5, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001824123.5

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

NCBI 1000 Genomes Browser:

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

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]

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

Citations

PubMed

SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas.

Korpershoek E, Favier J, Gaal J, Burnichon N, van Gessel B, Oudijk L, Badoual C, Gadessaud N, Venisse A, Bayley JP, van Dooren MF, de Herder WW, Tissier F, Plouin PF, van Nederveen FH, Dinjens WN, Gimenez-Roqueplo AP, de Krijger RR.

J Clin Endocrinol Metab. 2011 Sep;96(9):E1472-6. doi: 10.1210/jc.2011-1043. Epub 2011 Jul 13.

PubMed [citation]

PMID:: 21752896

A comprehensive next generation sequencing-based genetic testing strategy to improve diagnosis of inherited pheochromocytoma and paraganglioma.

Rattenberry E, Vialard L, Yeung A, Bair H, McKay K, Jafri M, Canham N, Cole TR, Denes J, Hodgson SV, Irving R, Izatt L, Korbonits M, Kumar AV, Lalloo F, Morrison PJ, Woodward ER, Macdonald F, Wallis Y, Maher ER.

J Clin Endocrinol Metab. 2013 Jul;98(7):E1248-56. doi: 10.1210/jc.2013-1319. Epub 2013 May 10.

PubMed [citation]

PMID:: 23666964

See all PubMed Citations (7)

Details of each submission

From DASA, SCV002073763.1

#	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

Last Updated: Sep 29, 2024

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