5-251427-C-T

Variant names:

• chr5-251427-C-T
• rs200397144
• NM_004168.4:c.1753C>T

Variant summary

Our verdict is Pathogenic. The variant received 24 ACMG points: 24P and 0B. PS1_Very_Strong PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_004168.4(SDHA):​c.1753C>T​(p.Arg585Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R585Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: SDHA NM_004168.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 U:2
• Conservation: PhyloP100: 5.78
• Publications: 15 publications found

Genes affected

SDHA (HGNC:10680): (succinate dehydrogenase complex flavoprotein subunit A) This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

SDHA Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• pheochromocytoma/paraganglioma syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• mitochondrial complex II deficiency, nuclear type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• neurodegeneration with ataxia and late-onset optic atrophy

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics, ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• gastrointestinal stromal tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex II deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1GG

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000286001 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 24 ACMG points.

• PS1: Transcript NM_004168.4 (SDHA) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 37 uncertain in NM_004168.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-251428-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 239658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 5-251427-C-T is Pathogenic according to our data. Variant chr5-251427-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 160358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4	c.1753C>T	p.Arg585Trp	missense_variant	Exon 13 of 15	ENST00000264932.11	NP_004159.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11	c.1753C>T	p.Arg585Trp	missense_variant	Exon 13 of 15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.*486C>T		non_coding_transcript_exon_variant	Exon 12 of 24			ENSP00000499215.1
ENSG00000286001	ENST00000651543.1	n.*486C>T		3_prime_UTR_variant	Exon 12 of 24			ENSP00000499215.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 250906 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461654 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727136

African (AFR) AF: 0.0000598 AC: 2 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111838

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152154 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000177 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 16, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 22517557, 28196207, 22904323, 27011036, 29177515, 23666964, 28546994, 28500238, 25720320, 25394176, 32621582, 29978154, 30050099, 30877234, 20301715, 26198225, 36980917, 21752896, 35731023, 35171114, 35988656, 36593350, 38473309, 39321216) -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Pheochromocytoma/paraganglioma syndrome 5 Pathogenic:2 Uncertain:1

Sep 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 01, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Apr 24, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30050099, 28546994, 21752896, 23666964]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Neurodegeneration with ataxia and late-onset optic atrophy Pathogenic:2

Sep 23, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 05, 2022

DASA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dilated cardiomyopathy 1GG Pathogenic:1

Feb 19, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 585 of the SDHA protein (p.Arg585Trp). This variant is present in population databases (rs200397144, gnomAD 0.005%). This missense change has been observed in individuals with paragangliomas and pheochromocytomas (PMID: 21752896, 23666964, 25720320, 28500238, 29177515, 30050099; internal data). ClinVar contains an entry for this variant (Variation ID: 160358). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SDHA protein function with a positive predictive value of 95%. This variant disrupts the p.Arg585 amino acid residue in SDHA. Other variant(s) that disrupt this residue have been observed in individuals with SDHA-related conditions (PMID: 30877234), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 25, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R585W pathogenic mutation (also known as c.1753C>T), located in coding exon 13 of the SDHA gene, results from a C to T substitution at nucleotide position 1753. The arginine at codon 585 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been identified in multiple individuals with paraganglioma, pheochromocytoma or gastrointestinal stromal tumor (Korpershoek E et al. J. Clin. Endocrinol. Metab. 2011 Sep;96:E1472-6; Rattenberry E et al. J. Clin. Endocrinol. Metab. 2013 Jul;98:E1248-56; Papathomas TG et al. Mod. Pathol. 2015 Jun;28:807-21; Boikos SA et al. JAMA Oncol, 2016 Jul;2:922-8; Casey RT et al. Mol. Genet. Genomic Med. 2017 May;5:237-250; Tufton N et al. Endocr. Relat. Cancer 2017 Jul;24:L43-L49; van der Tuin K et al. J. Clin. Endocrinol. Metab. 2018 Feb;103:438-445; Richter S et al. Genet Med, 2019 03;21:705-717). Another variant at the same codon, p.R585Q (c.1754G>A), has been detected in multiple individuals with paraganglioma or pheochromocytoma (Currás-Freixes M et al. J Med Genet, 2015 Oct;52:647-56; Ben Aim L et al. J Med Genet, 2019 08;56:513-520; Ambry internal data). Based on internal structural analysis, p.R585W is anticipated to result in a decrease in structural stability (Inaoka DK et al. Int J Mol Sci, 2015 Jul;16:15287-308). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Dilated cardiomyopathy 1GG;C3279992:Pheochromocytoma/paraganglioma syndrome 5;C5543254:Neurodegeneration with ataxia and late-onset optic atrophy;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1

Apr 08, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leigh syndrome;C3150898:Dilated cardiomyopathy 1GG;C3279992:Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.62	D;D;.;D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.3	.;H;.;.
PhyloP100		5.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.0	.;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.99
MVP		0.97
MPC		1.4
ClinPred		1.0	D
GERP RS		3.8
PromoterAI		-0.028	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.95
gMVP		0.97
Mutation Taster		=35/65	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200397144; hg19: chr5-251542; COSMIC: COSV53768691; COSMIC: COSV53768691;