rs387906358

chr11-112088883-ATC-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_003002.4(SDHD):c.191_192del(p.Leu64ProfsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S63S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHD NM_003002.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.44

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-112088883-ATC-A is Pathogenic according to our data. Variant chr11-112088883-ATC-A is described in ClinVar as [Pathogenic]. Clinvar id is 6904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112088883-ATC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHD	NM_003002.4	c.191_192del	p.Leu64ProfsTer4	frameshift_variant	3/4	ENST00000375549.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHD	ENST00000375549.8	c.191_192del	p.Leu64ProfsTer4	frameshift_variant	3/4	1	NM_003002.4	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

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 04, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6904). This premature translational stop signal has been observed in individual(s) with paraganglioma (PMID: 11391796, 15235042, 19454582, 23902947). 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.Leu64Profs*4) 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). -

Paragangliomas 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2001

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 25, 2016

This deletion of two nucleotides in SDHD is denoted c.191_192delTC at the cDNA level and p.Leu64ProfsX4 (L64PfsX4) at the protein level. The normal sequence, with the bases that are deleted in braces, is TCTC[TC]CACT. The deletion causes a frameshift which changes a Leucine to a Proline at codon 64, and creates a premature stop codon at position 4 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. SDHD c.191_192delTC tracked with disease in a large Australian family with hereditary paraganglioma (Badenhop 2001), and has been reported in multiple individuals with paraganglioma, including those with an apparently sporadic tumor (Burnichon 2009, Neumann 2009, Jafri 2013, Curras-Freixes 2015). We consider this variant to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2018

The c.191_192delTC variant, located in coding exon 3 of the SDHD gene, results from a deletion of two nucleotides at nucleotide positions 191 to 192, causing a translational frameshift with a predicted alternate stop codon (p.L64Pfs*4). This alteration has been reported in individuals with familial paraganglioma (Badenhop RF et al. Genes Chromosomes Cancer. 2001 Jul;31:255-63; Badenhop RF et al. J. Med. Genet. 2004 Jul;41:e99; Cascón A et al. J. Clin. Endocrinol. Metab. 2009 May;94:1701-5). It has also been reported in individuals with apparently sporadic paraganglioma (Amar L et al. J. Clin. Oncol. 2005 Dec;23:8812-8; Currás-Freixes M et al. J. Med. Genet. 2015 Oct;52:647-56). Multiple cohort studies of patients with parangliomas have also identified this variant (Neumann HP et al. Cancer Res. 2009 Apr;69:3650-6; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94:2817-27; Merlo A et al. J. Clin. Endocrinol. Metab. 2013 Oct;98:E1661-6; Jafri M et al. Clin. Endocrinol. (Oxf). 2013 Jun;78:898-906; de Cubas AA et al. Endocr. Relat. Cancer. 2013 Aug;20:477-93; Andrews KA et al. J. Med. Genet. 2018 Jun;55:384-394). 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

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: rs387906358; hg19: chr11-111959607;