Genetic Variant SDHD:p.Arg22* (chr11-112087868-C-T) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_003002.4(SDHD):c.64C>T(p.Arg22*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,576 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 (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SDHD
NM_003002.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 1.95

Variant links:

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 links:

ENSG00000255292 (HGNC:):

ENSG00000255292 links:

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ACMG classification

Classification made for transcript

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 43 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-112087868-C-T is Pathogenic according to our data. Variant chr11-112087868-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112087868-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHD	NM_003002.4 link	c.64C>T	p.Arg22*	stop_gained	Exon 2 of 4	ENST00000375549.8	NP_002993.1	O14521-1A0A0S2Z4J3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8 link	c.64C>T	p.Arg22*	stop_gained	Exon 2 of 4	1	NM_003002.4	ENSP00000364699.3		O14521-1
ENSG00000255292	ENST00000532699.1 link	n.64C>T		non_coding_transcript_exon_variant	Exon 2 of 6	3		ENSP00000456434.1		H3BRW5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459576

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726282

show subpopulations

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:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Paragangliomas 1

Pathogenic:2

Dec 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 21, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

Jun 04, 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.Arg22*) 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/or pheochromocytoma (PMID: 11391798, 11605159, 16317055, 19258401, 21348866, 22241717, 22517554). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6903). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -

Pheochromocytoma

Pathogenic:1

Jan 23, 2014

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Feb 22, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted SDHD c.64C>T at the cDNA level and p.Arg22Ter (R22X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in multiple individuals and families with hereditary paraganglioma/pheochromocytoma (Gimenez-Roqueplo 2001, Taschner 2001, Amar 2005, Lefebvre 2012, Piccini 2012) and is considered pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Sep 28, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R22* pathogenic mutation (also known as c.64C>T), located in coding exon 2 of the SDHD gene, results from a C to T substitution at nucleotide position 64. This changes the amino acid from an arginine to a stop codon within coding exon 2. This mutation has been reported in numerous individuals with a personal and/or family history of paraganglioma and/or pheochromocytoma (PGL-PCC) (Amar L et al. J. Clin. Oncol. 2005 Dec; 23(34):8812-8; Benn DE et al. J. Clin. Endocrinol. Metab. 2006 Mar; 91(3):827-36; Piccini V et al. Endocr. Relat. Cancer. 2012 Apr; 19(2):149-55; Cascón A et al. J. Clin. Endocrinol. Metab. 2009 May; 94(5):1701-5; Taschner PE et al. Genes Chromosomes Cancer. 2001 Jul; 31(3):274-81; Andrews KA et al. J. Med. Genet. 2018 Jun;55:384-394). A study including somatic and germline DNA analyses, cosegregation analyses, enzyme function studies and gene expression studies concluded that this mutation is associated with a complete loss of mitochondrial complex II activity and a high expression of angiogenic factors (Gimenez-Roqueplo AP et al. Am. J. Hum. Genet. 2001 Dec; 69(6):1186-97). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Hereditary pheochromocytoma-paraganglioma

Pathogenic:1

Feb 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.64C>T (p.Arg22*) variant in the exon 2 of SDHD gene creates a premature termination codon that is predicted to lead to an absent or truncated protein product. This variant has been identified in many individuals with paragangliomas (PMID: 11391798, 11605159, 16317055, 21348866, 22241717, 30050099, 32035780), and has been shown to segregate with disease in multiple family members (PMID 11605159). Loss-of-function variants in SDHD gene are known to be pathogenic (PMID: 10657297, 12111639, 11343322). This variant was found to be absent in the general population database (gnomAD). Therefore, the c.64C>T (p.Arg22*) variant in SDHD gene is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.0068

FATHMM_MKL

Benign

0.36

Vest4

0.85

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.22

Position offset: -11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over