rs140736646

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_004168.4(SDHA):c.133G>A(p.Ala45Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000372 in 1,613,408 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00058 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

SDHA
NM_004168.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:8

Conservation

PhyloP100: 2.87

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019135922).

BP6

Variant 5-223551-G-A is Benign according to our data. Variant chr5-223551-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224947.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=2, Uncertain_significance=7}. Variant chr5-223551-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000578 (88/152328) while in subpopulation AMR AF= 0.0036 (55/15298). AF 95% confidence interval is 0.00284. There are 1 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHA	NM_004168.4 linkuse as main transcript	c.133G>A	p.Ala45Thr	missense_variant	2/15	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.133G>A	p.Ala45Thr	missense_variant	2/15	1	NM_004168.4	ENSP00000264932	P1	P31040-1

Frequencies

GnomAD3 genomes

AF:

0.000578

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

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:

0.000441

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000426

AC:

107

AN:

251182

Hom.:

AF XY:

0.000471

AC XY:

AN XY:

135744

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000855

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000350

AC:

512

AN:

1461080

Hom.:

Cov.:

AF XY:

0.000344

AC XY:

250

AN XY:

726934

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000168

Gnomad4 NFE exome

AF:

0.000396

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000578

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00360

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000403

Hom.:

Bravo

AF:

0.00106

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000552

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SDHA p.Ala45Thr variant was identified in the literature in patients with thoracic paraganglioma, kidney and thyroid cancer, and polyclonal B cell lymphocytosis (Casey_2017_PMID:28546994; Nicolas_2019_PMID:30680959; Burgener_2019_PMID:31527833). The variant was identified in dbSNP (ID: rs140736646) and ClinVar (classified as uncertain significance by Invitae, Illumina, Counsyl and Arora Lab, Fox Chase Cancer Center, and as likely benign by Ambry Genetics). The variant was identified in control databases in 108 of 268048 chromosomes at a frequency of 0.0004029 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 95 of 117876 chromosomes (freq: 0.000806), Other in 4 of 6700 chromosomes (freq: 0.000597), Latino in 6 of 35108 chromosomes (freq: 0.000171), European (Finnish) in 2 of 25106 chromosomes (freq: 0.00008) and African in 1 of 23618 chromosomes (freq: 0.000042), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Ala45 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional studies in patient cells expressing the p.A45T variant showed gain of function and caused excess production of IL-6 and a stronger hydrogen bond interaction between SDHA and SDHB compared to wildtype (Burgener_2019_PMID:31527833). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 28, 2023	BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2023	Observed in an individual with paraganglioma and in both affected and unaffected individuals from a family with renal and other cancers (Casey et al., 2017; Nicolas et al., 2019); Published functional studies demonstrate increased complex II-specific oxygen consumption rate and IL-6 production, suggesting a gain-of-function effect (Burgener et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28500238, 28873162, 28492532, 28546994, 30680959, 31273876, 31527833) -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 18, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SDHA: PS3:Supporting, BP4, BS1 -

Paragangliomas 5

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jul 12, 2022	The SDHA c.133G>A (p.Ala45Thr) missense change has a maximum subpopulation frequency of 0.076% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been reported in a 36-year-old male with a thoracic paraganglioma (PMID: 28546994) and in affected and unaffected individuals in a family with renal cancer (PMID: 30680959). The in silico tool REVEL predicts a benign effect on protein function. A functional assay demonstrated that expression of the mutant in a lymphoblastoid cell line increased complex II-specific oxygen consumption rate and IL-6 production, suggesting a gain-of-function effect (PMID: 31527833). Loss-of-function variants in SDHA are known to be associated with hereditary paraganglioma-pheochromocytoma syndrome (PMID: 20484225, 21752896). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 24, 2023	This variant is considered likely 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

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 16, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 06, 2019	This alteration is classified as likely 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. -

Mitochondrial complex II deficiency, nuclear type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hereditary renal cell carcinoma

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Arora Lab, Fox Chase Cancer Center

Feb 26, 2018

The p.Ala45Thr variant (rs140736646) was found by exome sequencing in two siblings affected by renal cancer. While this variant is most prevalent in Europeans (97/126426 in the ExAC dataset (Lek et al., 2016)), it was inherited from the mother who also carried, in homozygous state, non-rare SDHA variants linked to African ancestry. The SDHA protein is a nuclear encoded mitochondrial protein, synthesized with a cleavage pre-sequence (residues 1 to 42) and imported to the matrix through the presequence cleavage pathway. The residue 45 in the preprotein becomes residue 3 in the mature protein, which assembles into the SDH complex. Scores of pathogenicity are low but may not take into account possible effects of the substitution on the different steps of the presequence processing. Immunostaining of the renal tumor of one of the siblings showed reduction in SDHA and loss of SDHB. This is expected from SDHA deficient tumors but could result from other events. As this single case study is insufficient to conclude for pathogenicity, this variant is classified as VUS. -

Leigh syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

SDHA-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2023

The SDHA c.133G>A variant is predicted to result in the amino acid substitution p.Ala45Thr. This variant was reported in an individual with thoracic paraganglioma, although no evidence was provided to determine its pathogenicity (Casey et al. 2017. PubMed ID: 28546994). This variant was also reported in a family with a history of early-onset clear cell renal cell carcinoma; however, expression of SDHA was unaffected in tissue from the proband (Nicolas et al. 2019. PubMed ID: 30680959). This variant was also documented in an individual with persistent polyclonal B cell lymphocytosis and functional studies showed that this variant leads to enhanced succinate dehydrogenase activity and accumulation of fumarate, suggesting a gain-of-function mechanism (Burgener et al. 2019. PubMed ID: 31527833). This variant is reported in 0.076% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of benign, likely benign, and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/224947/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Aug 31, 2023

Variant summary: SDHA c.133G>A (p.Ala45Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 152210 control chromosomes, predominantly at a frequency of 0.0036 within the Latino subpopulation in the gnomAD database (gnomAD v3, genomes data), including 1 homozygote. c.133G>A has been reported in the literature in individuals affected with thoracic paraganglioma, renal and thyroid cancers and persistent polyclonal B cell lymphocytosis (Casey_2017, Nicolas_2019, Burgener_2019). These reports do not provide unequivocal conclusions about association of the variant with Neurodegeneration With Ataxia And Late-Onset Optic Atrophy. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Burgener_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31527833, 28546994, 30680959). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=6), likely benign (n=4) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Hereditary pheochromocytoma-paraganglioma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;T;.;.

Eigen

Benign

0.064

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.84

T;T;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.019

T;T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.7

.;L;.;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.1

.;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.11

.;T;T;T

Sift4G

Benign

0.14

T;T;T;T

Polyphen

0.0030, 0.0040

.;B;B;.

Vest4

0.11

MVP

0.81

MPC

0.47

ClinPred

0.070

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.65

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