rs140736646

Variant names:

• chr5-223551-G-A
• rs140736646
• NM_004168.4:c.133G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-223551-G-A
• chr5-223551-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A45P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00058 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: SDHA NM_004168.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:8
• Conservation: PhyloP100: 2.87
• Publications: 7 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: Benign. The variant received -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 VariationId is 224947.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4	c.133G>A	p.Ala45Thr	missense_variant	Exon 2 of 15	ENST00000264932.11	NP_004159.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11	c.133G>A	p.Ala45Thr	missense_variant	Exon 2 of 15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.133G>A		non_coding_transcript_exon_variant	Exon 2 of 24			ENSP00000499215.1

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 88 AN: 152210 Hom.: 1 Cov.: 33

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

GnomAD2 exomes AF: 0.000426 AC: 107 AN: 251182 AF XY: 0.000471

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 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.: 0 Cov.: 30 AF XY: 0.000344 AC XY: 250 AN XY: 726934

African (AFR) AF: 0.0000299 AC: 1 AN: 33466

American (AMR) AF: 0.000626 AC: 28 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86228

European-Finnish (FIN) AF: 0.000168 AC: 9 AN: 53418

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

European-Non Finnish (NFE) AF: 0.000396 AC: 440 AN: 1111304

Other (OTH) AF: 0.000530 AC: 32 AN: 60362

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152328 Hom.: 1 Cov.: 33 AF XY: 0.000631 AC XY: 47 AN XY: 74488

African (AFR) AF: 0.0000241 AC: 1 AN: 41578

American (AMR) AF: 0.00360 AC: 55 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68030

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000422 Hom.: 0

Bravo AF: 0.00106

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000552 AC: 67

EpiCase AF: 0.000545

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:2

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SDHA: PS3:Supporting, BP4, BS1

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

Nov 18, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 05, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Mar 28, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4

Pheochromocytoma/paraganglioma syndrome 5 Uncertain:2 Benign:1

Mar 04, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 14, 2016

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 benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 06, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jul 16, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, 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.

Leigh syndrome Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, 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

Feb 26, 2018

Arora Lab, Fox Chase Cancer Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

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.

SDHA-related disorder Uncertain:1

Dec 20, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Aug 31, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

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

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary pheochromocytoma-paraganglioma Benign:1

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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;.;.
Eigen	Benign	0.064
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.019	T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.0	.;L;.;L
PhyloP100		2.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.0	.;N;N;N
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;T;T;T
Sift4G	Benign	0.14	T;T;T;T
Vest4		0.11
ClinPred		0.070	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.65
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs140736646; hg19: chr5-223666; COSMIC: COSV53768416; COSMIC: COSV53768416;