11-112094823-TACTG-T

Position:

• chr11-112094823-TACTG-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_003002.4(SDHD):​c.337_340del​(p.Asp113MetfsTer21) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHD NM_003002.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.58

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-112094823-TACTG-T is Pathogenic according to our data. Variant chr11-112094823-TACTG-T is described in ClinVar as [Pathogenic]. Clinvar id is 6912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112094823-TACTG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHD	NM_003002.4	c.337_340del	p.Asp113MetfsTer21	frameshift_variant	4/4	ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.337_340del	p.Asp113MetfsTer21	frameshift_variant	4/4	1	NM_003002.4	ENSP00000364699	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paragangliomas 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 17, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2018	This deletion of four nucleotides in SDHD is denoted c.337_340delGACT at the cDNA level and p.Asp113MetfsX21 (D113MfsX21) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TACT[delGACT]ATGT. The deletion causes a frameshift, which changes an Aspartic Acid to a Methionine at codon 113, and creates a premature stop codon at position 21 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation as the last 47 amino acids are no longer translated. The disrupted region includes the helical transmembrane topological domain and the ubiquinone binding site (UniProt). This variant, also known as SDHD c.334_337delACTG, is a recurrent variant that has been reported in many individuals with early-onset and/or multiple paragangliomas/pheochromocytomas, and has been shown to track with disease in several families (Cascon 2002, Velasco 2005, Benn 2006, Lima 2007, Hermsen 2010, Lefebvre 2012). Paragangliomas from individuals carrying this variant have demonstrated loss of SDHB by IHC, and functional assays have shown that this variant results in a significant reduction of SDH enzyme activity and SDHB protein expression (Rapizzi 2012, Pai 2014). We consider this variant to be pathogenic. Of note, variants in the SDHD gene exhibit a parent-of-origin effect and, if shown to be pathogenic, typically cause symptoms only if inherited from the father. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

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

Apr 25, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6912). This variant is also known as 13732delGACT. This premature translational stop signal has been observed in individuals with paragangliomas and/or pheochromocytomas (PMID: 12111639, 17848412, 21348866, 22517554, 27539324). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp113Metfs*21) in the SDHD gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the SDHD protein. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2021

The c.337_340delGACT pathogenic mutation, located in coding exon 4 of the SDHD gene, results from a deletion of 4 nucleotides at nucleotide positions 337 to 340, causing a translational frameshift with a predicted alternate stop codon (p.D113Mfs*21). This variant has been reported in many individuals with paragangliomas and/or pheochromocytomas (Cascon A et al. Eur J Hum Genet, 2002 Aug;10:457-61; Neumann HP et al. JAMA, 2004 Aug;292:943-51; Amar L et al. J Clin Oncol, 2005 Dec;23:8812-8; Velasco A et al. Diagn Mol Pathol, 2005 Jun;14:109-14; Benn DE et al. J Clin Endocrinol Metab, 2006 Mar;91:827-36; Castellano M et al. Ann N Y Acad Sci, 2006 Aug;1073:156-65; Lima J et al. J Clin Endocrinol Metab, 2007 Dec;92:4853-64; Sevilla MA et al. Otolaryngol Head Neck Surg, 2009 May;140:724-9; Hermsen MA et al. Cell Oncol, 2010 Jan;32:275-83; Hensen EF et al. Clin Genet, 2012 Mar;81:284-8; Lefebvre S et al. Horm Metab Res, 2012 May;44:334-8; Pai R et al. APMIS, 2014 Nov;122:1130-5; Pandit R et al. Eur J Endocrinol, 2016 Oct;175:311-23). This variant is also referred to as SDHD 13732delGACT and SDHD c.334_337delACTG in the literature. This alteration occurs at the 3' terminus of theSDHD gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 29% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C3494181:Paragangliomas 1;C5436934:Mitochondrial complex 2 deficiency, nuclear type 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587776648; hg19: chr11-111965547;