11-112087916-C-T

Position:

• chr11-112087916-C-T

Variant summary

Our verdict is Pathogenic. Variant got 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 (★★). 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:11 O:1
• Conservation: PhyloP100: 3.35

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]

ENSG00000255292 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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 id is 6893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112087916-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHD	NM_003002.4	c.112C>T	p.Arg38*	stop_gained	2/4	ENST00000375549.8	NP_002993.1

Ensembl

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Pathogenic:5 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 07, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 15, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 01, 2017	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. -
Pathogenic, no assertion criteria provided	research	Section on Medical Neuroendocrinolgy, National Institutes of Health	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 30, 2022	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. -

Paragangliomas 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 09, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jan 30, 2019	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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 14, 2024	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. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 18, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6893). 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). This variant is not present in population databases (gnomAD no frequency). 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). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 31, 2022

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 mutation has been reported in multiple individuals diagnosed with pheochromocytoma(s) and/or extra-adrenal paraganglioma(s) (Baysal BE et al. Science 2000 Feb;287(5454):848-51; Gimm O et al. Cancer Res. 2000 Dec;60(24):6822-5; Baysal BE et al. J. Med. Genet. 2002 Mar;39(3):178-83; Neumann HP et al. N. Engl. J. Med. 2002 May;346(19):1459-66; Erlic Z et al. Clin. Cancer Res. 2009 Oct;15(20):6378-85; Lodish MB et al. Endocr. Relat. Cancer 2010 Sep;17(3):581-8). One study identified this mutation in an unaffected individual as well as in his two children who were both affected with paragangliomas (Fish JH et al. Head Neck 2007 Sep;29(9):864-73). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration 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
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.77	D
Vest4		0.87
GERP RS		3.9

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

Other links and lift over

dbSNP: rs80338843; hg19: chr11-111958640;