rs104894309

chr11-112086940-C-Achr11-112086940-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.33C>A(p.Cys11Ter) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. C11C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHD NM_003002.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.586

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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 122 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-112086940-C-A is Pathogenic according to our data. Variant chr11-112086940-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 6915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112086940-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHD	NM_003002.4	c.33C>A	p.Cys11Ter	stop_gained	1/4	ENST00000375549.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHD	ENST00000375549.8	c.33C>A	p.Cys11Ter	stop_gained	1/4	1	NM_003002.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paragangliomas 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 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 09, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 28, 2021	- -

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

Oct 10, 2022

ClinVar contains an entry for this variant (Variation ID: 6915). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with pheochromocytoma and/or paraganglioma (PMID: 12000816, 18826997, 29386252). It is commonly reported in individuals of Polish ancestry (PMID: 12000816, 18826997, 29386252). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys11*) 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). -

Pheochromocytoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Dec 09, 2021

Criteria applied: PVS1, PS4_MOD, PM2_SUP -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2022

The p.C11* pathogenic mutation (also known as c.33C>A), located in coding exon 1 of the SDHD gene, results from a C to A substitution at nucleotide position 33. This changes the amino acid from a cysteine to a stop codon within coding exon 1 (p.C11*). This mutation has been reported in multiple individuals diagnosed with pheochromocytoma(s) and/or extra-adrenal paraganglioma(s) (Neumann HP et al. N. Engl. J. Med. 2002 May;346(19):1459-66; Peczkowska M et al. J. Clin. Endocrinol. Metab. 2008 Dec;93(12):4818-25; Michaowska I et al. Neuroendocrinology. 2015 Mar;101:321-30; Michaowska I et al. Kardiochir Torakochirurgia Pol. 2016 Sep;13:276-282). Peczkowaka and colleagues analyzed numerous p.C11* carrier families ascertained through the European-American PGL-PCC registry. In this series, the penetrance of head and neck PGLs in mutation carriers was 100% by age 54 and haplotype analysis data supported p.C11* as a founder mutation of Polish origin (Peczkowska M et al. J. Clin. Endocrinol. Metab. 2008 Dec;93(12):4818-25). 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	0.32
Cadd	Pathogenic	35
Dann	Uncertain	0.98
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.40	N
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.76
GERP RS		5.2
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs104894309; hg19: chr11-111957664;