11-112088991-CCTCA-C

Position:

• chr11-112088991-CCTCA-C

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.298_301delACTC​(p.Thr100fs) 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:3
• Conservation: PhyloP100: 7.54

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]

ENSG00000255292 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 20 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-112088991-CCTCA-C is Pathogenic according to our data. Variant chr11-112088991-CCTCA-C is described in ClinVar as [Pathogenic]. Clinvar id is 186590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112088991-CCTCA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHD	NM_003002.4	c.298_301delACTC	p.Thr100fs	frameshift_variant	3/4	ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.298_301delACTC	p.Thr100fs	frameshift_variant	3/4	1	NM_003002.4	ENSP00000364699.3
ENSG00000255292	ENST00000532699.1	n.298_301delACTC		non_coding_transcript_exon_variant	3/6	3		ENSP00000456434.1

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:3

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 20, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SDHD protein in which other variant(s) (p.Leu128Phefs*7) have been determined to be pathogenic (PMID: 11897817). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 186590). This premature translational stop signal has been observed in individual(s) with paragangliomas and pheochromocytomas (PMID: 22170724). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr100Phefs*34) in the SDHD gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 60 amino acid(s) of the SDHD protein. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 15, 2014

The c.298_301delACTC pathogenic mutation, located in coding exon 3 of the SDHD gene, results from a deletion of 4 nucleotides between positions 298 and 301, causing a translational frameshift with a predicted alternate stop codon. This mutation was identified in a male proband with multiple PGLs in the neck, thorax, and abdomen, a GH-secreting pituitary adenoma, and a family history of PGL (Xekouki, P et al. J Clin Endocrinol Metab. 2012 Mar;97(3):E357-66). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Section on Medical Neuroendocrinolgy, National Institutes of Health

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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: rs786203067; hg19: chr11-111959715;