chr5-251439-C-T

Position:

chr5-251439-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_004168.4(SDHA):c.1765C>T(p.Arg589Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,613,864 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 (★★).

Frequency

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

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

SDHA
NM_004168.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 4.66

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.948

PP5

Variant 5-251439-C-T is Pathogenic according to our data. Variant chr5-251439-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-251439-C-T is described in Lovd as [Pathogenic]. Variant chr5-251439-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHA	NM_004168.4 linkuse as main transcript	c.1765C>T	p.Arg589Trp	missense_variant	13/15	ENST00000264932.11	NP_004159.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11 linkuse as main transcript	c.1765C>T	p.Arg589Trp	missense_variant	13/15	1	NM_004168.4	ENSP00000264932	P1	P31040-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

251004

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135690

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461658

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000322

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Paragangliomas 5

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Sep 13, 2023	This variant is present in population databases (rs387906780, gnomAD 0.007%). This missense change has been observed in individuals with paraganglioma or gastrointestinal stromal tumors (PMID: 20484225, 22955521, 25405498, 28546994). ClinVar contains an entry for this variant (Variation ID: 30132). Experimental studies have shown that this missense change affects SDHA function (PMID: 20484225, 21505157, 23043141). This variant disrupts the p.Arg589 amino acid residue in SDHA. Other variant(s) that disrupt this residue have been observed in individuals with SDHA-related conditions (PMID: 23612575, 28546994), which suggests that this may be a clinically significant amino acid residue. Therefore, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 08, 2024	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 27847310]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 20484225, 28070496, 30949620]. -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2022	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect: absent SDH activity and reduced protein expression (Burnichon et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28798025, 23043141, 21505157, 23154507, 19628817, 34014604, 22955521, 29978154, 28546994, 25405498, 20484225) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	SDHA: PS3, PM1, PM5, PP3, BP1 -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 16, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 589 of the SDHA protein (p.Arg589Trp). This variant is present in population databases (rs387906780, gnomAD 0.007%). This missense change has been observed in individuals with paraganglioma or gastrointestinal stromal tumors (PMID: 20484225, 22955521, 25405498, 28546994). ClinVar contains an entry for this variant (Variation ID: 30132). 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 80%. Experimental studies have shown that this missense change affects SDHA function (PMID: 20484225, 21505157, 23043141). This variant disrupts the p.Arg589 amino acid residue in SDHA. Other variant(s) that disrupt this residue have been observed in individuals with SDHA-related conditions (PMID: 23612575, 28546994), 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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 26, 2024

- -

Gastrointestinal stromal tumor

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

“Giorgio Prodi” Cancer Research Center, University of Bologna

Oct 01, 2021

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 11, 2022

The p.R589W pathogenic mutation (also known as c.1765C>T), located in coding exon 13 of the SDHA gene, results from a C to T substitution at nucleotide position 1765. The arginine at codon 589 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been detected in individuals with paraganglioma or gastrointestinal stromal tumor (Burnichon N et al. Hum. Mol. Genet., 2010 Aug;19:3011-20; Casey RT et al. Mol Genet Genomic Med, 2017 May;5:237-250; Ambry internal data). This alteration was also reported in gastrointestinal stromal tumor tissues (Pantaleo MA et al. J. Natl. Cancer Inst., 2011 Jun;103:983-7; Wagner AJ et al. Mod. Pathol., 2013 Feb;26:289-94). Several functional studies indicate that this mutation impairs succinate dehydrogenase activity and likely interferes with SDHAF2 binding which is essential for FAD insertion into SDHA (Hao HX et al. Science, 2009 Aug;325:1139-42; Burnichon N et al. Hum. Mol. Genet., 2010 Aug;19:3011-20; Kim HJ et al. J. Biol. Chem., 2012 Nov;287:40670-9; Huang S et al. Plant Signal Behav, 2013 Feb;8:e22815; Lorendeau D et al. Metab. Eng., 2017 09;43:187-197). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;D;.;D

Eigen

Benign

0.16

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

5.2

.;H;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-7.0

.;D;D;D

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

.;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.99

MVP

0.90

MPC

1.3

ClinPred

1.0

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.98

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