rs6962

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004168.4(SDHA):c.1969G>A(p.Val657Ile) variant causes a missense change. The variant allele was found at a frequency of 0.128 in 1,605,264 control chromosomes in the GnomAD database, including 11,138 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V657A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.18 ( 2763 hom., cov: 34)

Exomes 𝑓: 0.12 ( 8375 hom. )

Consequence

SDHA
NM_004168.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 4.70

Publications

51 publications found

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 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

SDHA links:

ENSG00000286001 (HGNC:):

ENSG00000286001 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011221588).

BP6

Variant 5-256394-G-A is Benign according to our data. Variant chr5-256394-G-A is described in ClinVar as Benign. ClinVar VariationId is 130279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4 link	c.1969G>A	p.Val657Ile	missense_variant	Exon 15 of 15	ENST00000264932.11	NP_004159.2	P31040-1A0A024QZ30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SDHA	ENST00000264932.11 link	c.1969G>A	p.Val657Ile	missense_variant	Exon 15 of 15	1	NM_004168.4	ENSP00000264932.6	P31040-1
ENSG00000286001	ENST00000651543.1 link	n.*702G>A		non_coding_transcript_exon_variant	Exon 14 of 24			ENSP00000499215.1	A0A494C1T6
ENSG00000286001	ENST00000651543.1 link	n.*702G>A		3_prime_UTR_variant	Exon 14 of 24			ENSP00000499215.1	A0A494C1T6

Frequencies

GnomAD3 genomes

AF:

0.176

AC:

26620

AN:

151644

Hom.:

2756

Cov.:

show subpopulations

Gnomad AFR

AF:

0.316

Gnomad AMI

AF:

0.296

Gnomad AMR

AF:

0.179

Gnomad ASJ

AF:

0.156

Gnomad EAS

AF:

0.0559

Gnomad SAS

AF:

0.0850

Gnomad FIN

AF:

0.0812

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.120

Gnomad OTH

AF:

0.177

GnomAD2 exomes

AF:

0.131

AC:

32957

AN:

250898

AF XY:

0.126

show subpopulations

Gnomad AFR exome

AF:

0.324

Gnomad AMR exome

AF:

0.169

Gnomad ASJ exome

AF:

0.151

Gnomad EAS exome

AF:

0.0602

Gnomad FIN exome

AF:

0.0855

Gnomad NFE exome

AF:

0.123

Gnomad OTH exome

AF:

0.131

GnomAD4 exome

AF:

0.123

AC:

178656

AN:

1453502

Hom.:

8375

Cov.:

AF XY:

0.121

AC XY:

87874

AN XY:

723584

show subpopulations

African (AFR)

AF:

0.308

AC:

10168

AN:

32986

American (AMR)

AF:

0.163

AC:

7286

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.153

AC:

3980

AN:

26064

East Asian (EAS)

AF:

0.0476

AC:

1890

AN:

39680

South Asian (SAS)

AF:

0.0871

AC:

7500

AN:

86144

European-Finnish (FIN)

AF:

0.0873

AC:

4662

AN:

53390

Middle Eastern (MID)

AF:

0.101

AC:

582

AN:

5750

European-Non Finnish (NFE)

AF:

0.122

AC:

134748

AN:

1104814

Other (OTH)

AF:

0.131

AC:

7840

AN:

60060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.423

Heterozygous variant carriers

8231

16463

24694

32926

41157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5082

10164

15246

20328

25410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.176

AC:

26650

AN:

151762

Hom.:

2763

Cov.:

AF XY:

0.170

AC XY:

12640

AN XY:

74186

show subpopulations

African (AFR)

AF:

0.316

AC:

13026

AN:

41226

American (AMR)

AF:

0.178

AC:

2724

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.156

AC:

539

AN:

3466

East Asian (EAS)

AF:

0.0554

AC:

287

AN:

5178

South Asian (SAS)

AF:

0.0855

AC:

412

AN:

4818

European-Finnish (FIN)

AF:

0.0812

AC:

859

AN:

10582

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.120

AC:

8123

AN:

67920

Other (OTH)

AF:

0.174

AC:

367

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1068

2135

3203

4270

5338

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

268

536

804

1072

1340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.121

Hom.:

740

Bravo

AF:

0.196

TwinsUK

AF:

0.128

AC:

474

ALSPAC

AF:

0.129

AC:

496

ESP6500AA

AF:

0.326

AC:

1438

ESP6500EA

AF:

0.130

AC:

1117

ExAC

AF:

0.131

AC:

15857

Asia WGS

AF:

0.0970

AC:

341

AN:

3478

EpiCase

AF:

0.132

EpiControl

AF:

0.128

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 03, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mitochondrial complex II deficiency, nuclear type 1

Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Pheochromocytoma/paraganglioma syndrome 5

Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 11, 2025

Myriad Genetics, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Hereditary cancer-predisposing syndrome

Benign:2

Jan 08, 2025

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BA1+BP6 -

Nov 18, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified

Benign:1

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Leigh syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SDHA-related disorder

Benign:1

Jun 02, 2022

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary pheochromocytoma-paraganglioma

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.24

T;T;.;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.46

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.80

T;T;T;T

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;L;.;.

PhyloP100

4.7

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.45

.;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.33

.;T;T;T

Sift4G

Benign

0.58

T;T;T;T

Polyphen

0.021, 0.013

.;B;B;.

Vest4

0.15

MPC

0.41

ClinPred

0.017

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.031

gMVP

0.50

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over