rs104894308

chr11-112087933-G-A

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.129G>A(p.Trp43Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: SDHD NM_003002.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.05

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]

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 11-112087933-G-A is Pathogenic according to our data. Variant chr11-112087933-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112087933-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHD	NM_003002.4	c.129G>A	p.Trp43Ter	stop_gained	2/4	ENST00000375549.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHD	ENST00000375549.8	c.129G>A	p.Trp43Ter	stop_gained	2/4	1	NM_003002.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paragangliomas 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 29, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2008	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2021

This sequence change creates a premature translational stop signal (p.Trp43*) in the SDHD gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SDHD are known to be pathogenic (PMID: 19454582, 19802898). This variant has been reported to segregate with paraganglioma in a single family (PMID: 18211978) and also has been observed in unrelated individuals with paraganglioma (PMID: 12111639, 19454582, 18561749, 20098451) and gastrointestinal stromal tumor (PMID: 20098451). This variant has been described as a likely common cause of disease in the Spanish population (PMID: 19258401). ClinVar contains an entry for this variant (Variation ID: 6913). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 11, 2017

The SDHD c.129G>A, p.Trp43Ter variant (rs104894308) has been reported in multiple families with head and neck paraganglioma (Benn 2008, Cascon 2002, Timmers 2008), and segregating with affected individuals (Pigny 2008, Valesco 2005). It is listed as pathogenic in ClinVar (Variation ID: 6913), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Benn D et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab. 2006; 91(3):827-36. Cascon A et al. Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma. Eur J Hum Genet. 2002; 10(8):457-61. Pigny P et al. Paraganglioma after maternal transmission of a succinate dehydrogenase gene mutation. J Clin Endocrinol Metab. 2008; 93(5):1609-15. Timmers H et al. Mutations associated with succinate dehydrogenase D-related malignant paragangliomas. Clin Endocrinol (Oxf). 2008; 68(4):561-6. Velasco A et al. Mutation analysis of the SDHD gene in four kindreds with familial paraganglioma: description of one novel germline mutation. Diagn Mol Pathol. 2005; 14(2):109-14. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2018

The p.W43* pathogenic mutation (also known as c.129G>A) located in coding exon 2 of the SDHD gene, results from a G to A substitution at nucleotide position 129. This changes the amino acid from a tryptophan to a stop codon within coding exon 2. This pathogenic mutation has been identified in a patient with multiple paragangliomas (PGLs) and a family history of pheochromocytoma, and it has been predicted to lead to a protein that lacks the transmembrane, signal, and heme-binding domains (Cascon A et al. Eur. J. Hum. Genet. 2002 Aug; 10(8):457-61). The p.W43* pathogenic mutation has also been reported in a French female diagnosed with metastatic bilateral cartoid HNPGLs at age 22 who had no family history of PGLs (Timmers HJ et al. Clin. Endocrinol. (Oxf). 2008 Apr;68:561-6). 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	0.40
Cadd	Pathogenic	35
Dann	Uncertain	0.99
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.65	D
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.88
GERP RS		-0.018

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: rs104894308; hg19: chr11-111958657;