11-112087916-C-T

Variant names:

• chr11-112087916-C-T
• rs80338843
• NM_003002.4:c.112C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003002.4(SDHD):​c.112C>T​(p.Arg38*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,668 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R38R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SDHD NM_003002.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 3.35
• Publications: 16 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-112087916-C-T is Pathogenic according to our data. Variant chr11-112087916-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 6893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHD	NM_003002.4	c.112C>T	p.Arg38*	stop_gained	Exon 2 of 4	ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.112C>T	p.Arg38*	stop_gained	Exon 2 of 4	1	NM_003002.4	ENSP00000364699.3
ENSG00000255292	ENST00000532699.1	n.112C>T		non_coding_transcript_exon_variant	Exon 2 of 6	3		ENSP00000456434.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461668 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727152

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111822

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Pathogenic:6 Other:1

Aug 15, 2019

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Mar 01, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg38X variant in SDHD has been reported in at least 9 individuals with SD HD-associated cancers, segregated with disease in at least 10 affected relatives from multiple families (Gimm 2000, Baysal 2000;2002,Neumann 2004, Erlic 2009, B urnichon 2009, Hensen 2012, ClinVar ID#6893), and was absent from large populati on studies. This nonsense variant leads to a premature termination codon at posi tion 38, which is predicted to lead to a truncated or absent protein. Heterozygo us loss of function of the SDHD gene is an established disease mechanism in indi viduals with hereditary paragangliomas and pheochromocytomas. In summary, this v ariant meets criteria to be classified as pathogenic for hereditary paragangliom as and pheochromocytomas in an autosomal dominant manner based upon segregation studies and the predicted impact to the protein.

Mar 30, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SDHD c.112C>T (p.Arg38X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251472 control chromosomes (gnomAD). c.112C>T has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome and was shown to co-segregate with disease within families (e.g. Baysal_2000, Neumann_2002, Erlic_2009, Ding_2019). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Sep 23, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 2 of the SDHD gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with hereditary paranganglioma-pheochromocytoma syndrome (PMID: 11156372, 15328326, 19454582, 19825962, 21348866, 30484866, 30484866). It has been shown that this variant segregates with disease with the disease in one family (PMID: 30484866). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of SDHD function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Aug 07, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.112C>T (p.Arg38*) variant in the SDHD gene is located in exon 2 and introduces an early stop codon. It is predicted to result in an absent or disrupted protein product. This variant has been reported in multiple individuals affected with paraganglioma and pheochromocytoma (PMID: 10657297, 11156372, 11897817, 12000816, 15328326, 19825962, 19454582, 21348866, 30484866) and segregated with disease (PMID: 10657297, 19454582, 21348866, 30484866). Loss-of-function variants in SDHD gene are known to be pathogenic (PMID: 10657297, 12111639, 11343322). This variant has been classified as pathogenic by multiple submitters in ClinVar (ID: 6893). This variant is absent in the general population database (gnomAD). Therefore, this variant is classified as pathogenic.

Section on Medical Neuroendocrinolgy, National Institutes of Health

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

not provided Pathogenic:2

Apr 14, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SDHD c.112C>T (p.Arg38*) variant causes the premature termination of SDHD protein synthesis. This variant has been reported in the published literature in individuals with hereditary paraganglioma-pheochromocytoma (PMID: 34750850 (2022), 32971818 (2020), 26269449 (2015), 21348866 (2012), 19825962 (2009), 15328326 (2004), 12000816 (2002)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.

Aug 18, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10657297, 12000816, 19825962, 12811540, 21348866, 12351569, 26273102, 12205103, 8981955, 27867439, 27700540, 33219105, 25525159, 11156372, 25791839, 17563904, 12364472, 22517557, 20418362, 11897817, 11391798, 15328326, 19454582, 26269449, 15066320, 22566157, 28748451, 27073498, 32561571, 34750850)

Pheochromocytoma/paraganglioma syndrome 1 Pathogenic:2

May 09, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jan 30, 2019

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.112C>T (p.Arg38*) variant in the SDHD gene is located in exon 2 and introduces an early stop codon. It is predicted to result in an absent or disrupted protein product. This variant has been reported in multiple individuals affected with paraganglioma and pheochromocytoma (PMID: 10657297, 11156372, 11897817, 12000816, 15328326, 19825962, 19454582, 21348866, 30484866) and segregated with disease (PMID: 10657297, 19454582, 21348866, 30484866). Loss-of-function variants in SDHD gene are known to be pathogenic (PMID: 10657297, 12111639, 11343322). This variant has been classified as pathogenic by multiple submitters in ClinVar (ID: 6893). This variant is absent in the general population database (gnomAD). Therefore, this variant is classified as pathogenic.

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

Aug 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg38*) in the SDHD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHD are known to be pathogenic (PMID: 19454582, 19802898). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with paraganglioma and pheochromocytoma (PMID: 10657297, 11156372, 11897817, 12000816, 15328326, 19454582, 19825962, 21348866, 26269449). ClinVar contains an entry for this variant (Variation ID: 6893). For these reasons, this variant has been classified as Pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:1

May 27, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R38* pathogenic mutation (also known as c.112C>T), located in coding exon 2 of the SDHD gene, results from a C to T substitution at nucleotide position 112. This changes the amino acid from an arginine to a stop codon within coding exon 2. This variant was reported in individual(s) with features consistent with SDHD-related paraganglioma-pheochromocytoma syndrome (Baysal BE et al. Science, 2000 Feb;287:848-51; Gimm O et al. Cancer Res, 2000 Dec;60:6822-5; Neumann HP et al. N Engl J Med, 2002 May;346:1459-66; Fish JH et al. Head Neck, 2007 Sep;29:864-73; Erlic Z et al. Clin Cancer Res, 2009 Oct;15:6378-85; Lodish MB et al. Endocr Relat Cancer, 2010 Sep;17:581-8). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing; however, RNA studies have demonstrated that this alteration also results in an incomplete splice defect (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	40
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.;.;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.40
LIST_S2	Benign	0.0	.;.;.;.;.;.
MetaRNN	Benign	0.0	.;.;.;.;.;.
MutationAssessor	Benign	0.0	.;.;.;.;.;.
PhyloP100		3.4
PROVEAN	Benign	0.0	.;.;.;.;.;.
Sift	Pathogenic	0.0	.;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;.
Vest4		0.87
GERP RS		3.9
Mutation Taster		=7/193	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: rs80338843; hg19: chr11-111958640;