chr5-251427-C-T

Position:

chr5-251427-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3_StrongPP5

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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

SDHA
NM_004168.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11U:2

Conservation

PhyloP100: 5.78

Variant links:

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 links:

ENSG00000286001 (HGNC:):

ENSG00000286001 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 160358.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=3, Likely_pathogenic=5}. Variant chr5-251427-C-T is described in Lovd as [Likely_pathogenic]. Variant chr5-251427-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHA	NM_004168.4 linkuse as main transcript	c.1753C>T	p.Arg585Trp	missense_variant	13/15	ENST00000264932.11	NP_004159.2	P31040-1A0A024QZ30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SDHA	ENST00000264932.11 linkuse as main transcript	c.1753C>T	p.Arg585Trp	missense_variant	13/15	1	NM_004168.4	ENSP00000264932.6	P31040-1
ENSG00000286001	ENST00000651543.1 linkuse as main transcript	n.*486C>T		non_coding_transcript_exon_variant	12/24			ENSP00000499215.1	A0A494C1T6
ENSG00000286001	ENST00000651543.1 linkuse as main transcript	n.*486C>T		3_prime_UTR_variant	12/24			ENSP00000499215.1	A0A494C1T6

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250906

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135664

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1461654

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000761

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 02, 2025	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) -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Paragangliomas 5

Pathogenic:2Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2011	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 01, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 24, 2023	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

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 23, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	DASA	Feb 05, 2022	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. -

Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

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; Invitae). ClinVar contains an entry for this variant (Variation ID: 160358). 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 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. -

Dilated cardiomyopathy 1GG

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 19, 2024

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 2024

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. -

Leigh syndrome;C3150898:Dilated cardiomyopathy 1GG;C3279992:Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

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

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

5.3

.;H;.;.

PrimateAI

Pathogenic

0.89

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

GERP RS

3.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.95

gMVP

0.97

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over