11-112094969-G-T

Variant names:

• chr11-112094969-G-T
• rs201372601
• NM_003002.4:c.479G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM4 PP5

The NM_003002.4(SDHD):​c.479G>T​(p.Ter160Leuext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000931 in 1,610,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: SDHD NM_003002.4 stop_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:5
• Conservation: PhyloP100: 1.54
• Publications: 4 publications found

Genes affected

SDHD (HGNC:10683): (succinate dehydrogenase complex subunit D) This gene encodes a member of complex II of the respiratory chain, which is responsible for the oxidation of succinate. The encoded protein is one of two integral membrane proteins anchoring the complex to the matrix side of the mitochondrial inner membrane. Mutations in this gene are associated with the formation of tumors, including hereditary paraganglioma. Transmission of disease occurs almost exclusively through the paternal allele, suggesting that this locus may be maternally imprinted. There are pseudogenes for this gene on chromosomes 1, 2, 3, 7, and 18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2013]

SDHD Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• pheochromocytoma/paraganglioma syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Carney-Stratakis syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• mitochondrial complex II deficiency, nuclear type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• mitochondrial complex 2 deficiency, nuclear type 3

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• mitochondrial complex II deficiency

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intestinal cancer

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• mitochondrial disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000255292 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM4: Stoplost variant in NM_003002.4 Downstream stopcodon found after 170 codons.
• PP5: Variant 11-112094969-G-T is Pathogenic according to our data. Variant chr11-112094969-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 156154.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHD	NM_003002.4	c.479G>T	p.Ter160Leuext*?	stop_lost	Exon 4 of 4	ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.479G>T	p.Ter160Leuext*?	stop_lost	Exon 4 of 4	1	NM_003002.4	ENSP00000364699.3
ENSG00000255292	ENST00000532699.1	n.314+5958G>T		intron_variant	Intron 3 of 5	3		ENSP00000456434.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152180 Hom.: 0 Cov.: 32

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247668 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000823 AC: 12 AN: 1458320 Hom.: 0 Cov.: 29 AF XY: 0.00000827 AC XY: 6 AN XY: 725576

African (AFR) AF: 0.00 AC: 0 AN: 33392

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1110676

Other (OTH) AF: 0.00 AC: 0 AN: 60156

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15266

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Jul 16, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: reduced enzyme activities of the individual respiratory chains complexes in skeletal muscle and inability to restore the complex II assembly in a fibroblast cell line (PMID: 24367056); Stop codon loss and change to a leucine codon, leading to protein extension and the addition of 3 amino acid(s) at the C-terminus; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.X104LextX3; This variant is associated with the following publications: (PMID: 34012134, 33162331, 24367056) -

Apr 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:2

Dec 04, 2018

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SDHD c.479G>T (p.X160LeuextX3) changes the termination codon and is predicted to lead to an extended protein with additional 3 amino acids added to the normal C-terminus. The variant allele was found at a frequency of 4.1e-06 in 242834 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.479G>T has been reported in the literature in one individual affected with mitochondrial complex II deficiency in compound heterozygous state (Jackson_2014). This report does not provide unequivocal conclusions about association of the variant with Hereditary Paraganglioma-Pheochromocytoma Syndrome. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about causality of the variant (Jackson_2014). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Oct 20, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Extension variant reported in 1 proband with autosomal recessive encephalomyopathy and MT complex II deficiency - proband carried E69K on other allele. Complementation of a patient cell line supported the pathogenicity of the SDHD variants. -

Hereditary pheochromocytoma-paraganglioma Uncertain:2

-

Section on Medical Neuroendocrinolgy, National Institutes of Health

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is a termination codon variant that changes the translational stop signal of the SDHD gene to leucine and extends the length of the SDHD protein by 3 additional amino acids. A functional complementation experiment using patient fibroblasts harboring the SDHD c.205G>A p.(Glu69Lys) and SDHD c.479G>T p.*160Leuext*3 variants demonstrated that transduction with either mutant transcript was unable to rescue the reduced expression and activity of the succinate dehydrogenase complex, whereas transduction of the patient fibroblasts with the wild type SDHD cDNA transcript restored SDH activity. Mitochondrial complex II activity and levels were also significantly reduced in patient cells (PMID: 24367056). This variant has been reported in trans with another SDHD variant (c.205G>A, p.Glu69Lys) in a single individual with autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency (PMID: 24367056). The parents were heterozygous for one of the variants each and have been referred for tumor surveillance. Screening with 24 h measurements of blood pressure and urinary catecholamines of both parents was normal. The SDHD / c.479G>T / p.160Leuext3 variant has been observed in two individuals with paraganglioma at NIH (ClinVar, SCV000599548.1, personal communication). A similar stop loss variant in the SDHD gene, (c.479_480insGT, p.*160Trpext*8) has been identified in a patient with bilateral carotid paragangliomas (PMID: 31508186). The SDHD c.479G>T p.*160Leuext*3 variant has been identified in 1/247668 chromosomes in the general population by the Genome Aggregation Database (gnomAD). While the evidence may support a causal role in autosomal recessive mitochondrial complex II deficiency, the clinical significance with respect to autosomal dominant paraganglioma-pheochromocytoma syndrome is uncertain. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Mitochondrial complex 2 deficiency, nuclear type 3 Pathogenic:1

Mar 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Apr 04, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.479G>T variant (also known as p.*160Lext*3), located in coding exon 4 of the SDHD gene, results from a G to T substitution at nucleotide position 479, which is the second to last nucleotide of the SDHD gene. This alteration disrupts the stop codon of the SDHD gene and is predicted to preserve the native sequence while resulting in the elongation of the protein by 3 amino acids. The exact functional effect of the additional amino acids is unknown. This alteration has been reported as compound heterozygous with a second SDHD alteration, p.E69K, in an individual with autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency (Jackson CB et al. J. Med. Genet., 2014 Mar;51:170-5). Functional studies demonstrated that the introduction of this variant to patient cells was unable to recover complex II formation compared to a WT control (Jackson CB et al. J. Med. Genet., 2014 Mar;51:170-5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic in association with autosomal recessive mitochondrial complex II deficiency when present along with a second pathogenic or likely pathogenic variant on the other allele; however, the clinical significance in regards to paraganglioma-pheochromocytoma syndrome is unlikely. -

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 Uncertain:1

Jan 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change disrupts the translational stop signal of the SDHD mRNA. It is expected to extend the length of the SDHD protein by 3 additional amino acid residues. This variant is present in population databases (rs201372601, gnomAD 0.0009%). This protein extension has been observed in individual(s) with mitochondrial complex II deficiency (PMID: 24367056). ClinVar contains an entry for this variant (Variation ID: 156154). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this protein extension affects SDHD function (PMID: 24367056). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	0.0056	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	16
DANN	Benign	0.86
Eigen	Pathogenic	0.83
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		1.5
Vest4		0.27
GERP RS		3.9
Mutation Taster		=13/187	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs201372601; hg19: chr11-111965693; COSMIC: COSV65019826; COSMIC: COSV65019826;