rs1555187583

Positions:

• chr11-112094825-C-CT

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.336dup​(p.Asp113Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T112T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SDHD NM_003002.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.0750

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 is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 29 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-112094825-C-CT is Pathogenic according to our data. Variant chr11-112094825-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 547770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHD	NM_003002.4	c.336dup	p.Asp113Ter	frameshift_variant	4/4	ENST00000375549.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHD	ENST00000375549.8	c.336dup	p.Asp113Ter	frameshift_variant	4/4	1	NM_003002.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

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. This variant disrupts a region of the SDHD protein in which other variant(s) (p.Leu139Arg) have been determined to be pathogenic (PMID: 11343322, 15032977, 15328326; Invitae). 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: 547770). This variant is also known as 13732insT. This premature translational stop signal has been observed in individual(s) with paraganglioma (PMID: 11343322). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp113*) 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. -

Paragangliomas 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

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: rs1555187583; hg19: chr11-111965549;