rs878854591

Variant names:

• chr11-112088937-TC-T
• rs878854591
• NM_003002.4:c.242delC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003002.4(SDHD):​c.242delC​(p.Pro81ArgfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,220 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P81P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SDHD NM_003002.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.44
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• pheochromocytoma/paraganglioma syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Carney-Stratakis syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• mitochondrial complex II deficiency, nuclear type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• mitochondrial complex 2 deficiency, nuclear type 3

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• mitochondrial complex II deficiency

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intestinal cancer

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• mitochondrial disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000255292 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-112088937-TC-T is Pathogenic according to our data. Variant chr11-112088937-TC-T is described in CliVar as Pathogenic. Clinvar id is 239464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112088937-TC-T is described in CliVar as Pathogenic. Clinvar id is 239464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112088937-TC-T is described in CliVar as Pathogenic. Clinvar id is 239464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112088937-TC-T is described in CliVar as Pathogenic. Clinvar id is 239464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112088937-TC-T is described in CliVar as Pathogenic. Clinvar id is 239464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112088937-TC-T is described in CliVar as Pathogenic. Clinvar id is 239464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112088937-TC-T is described in CliVar as Pathogenic. Clinvar id is 239464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112088937-TC-T is described in CliVar as Pathogenic. Clinvar id is 239464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112088937-TC-T is described in CliVar as Pathogenic. Clinvar id is 239464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112088937-TC-T is described in CliVar as Pathogenic. Clinvar id is 239464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112088937-TC-T is described in CliVar as Pathogenic. Clinvar id is 239464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHD	NM_003002.4	c.242delC	p.Pro81ArgfsTer5	frameshift_variant	Exon 3 of 4	ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.242delC	p.Pro81ArgfsTer5	frameshift_variant	Exon 3 of 4	1	NM_003002.4	ENSP00000364699.3
ENSG00000255292	ENST00000532699.1	n.242delC		non_coding_transcript_exon_variant	Exon 3 of 6	3		ENSP00000456434.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Jan 30, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.242delC pathogenic mutation, located in coding exon 3 of the SDHD gene, results from a deletion of one nucleotide at nucleotide position 242, causing a translational frameshift with a predicted alternate stop codon (p.P81Rfs*5). This variant was reported in individual(s) with features consistent with SDHD-related paraganglioma-pheochromocytoma syndrome (Burnichon N et al. J Clin Endocrinol Metab, 2009 Aug;94:2817-27; Chew WHW et al. Mol Genet Genomic Med, 2017 Sep;5:602-607; Andrews KA et al. J Med Genet, 2018 Jun;55:384-394). 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. -

Oct 09, 2020

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 Pathogenic:1

Sep 22, 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.Pro81Argfs*5) 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 (PMID: 19454582). This variant is also known as c.242del*. ClinVar contains an entry for this variant (Variation ID: 239464). For these reasons, this variant has been classified as Pathogenic. -

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C3494181:Pheochromocytoma/paraganglioma syndrome 1 Pathogenic:1

Mar 17, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change deletes 1 nucleotide from exon 3 of the SDHD mRNA (c.242delC), causing a frameshift at codon 81. This creates a premature translational stop signal (p.Pro81Argfs*5) and is expected to result in an absent or disrupted protein product. Truncating variants in SDHD are known to be pathogenic. This particular truncation has been reported in the literature in a patient affected with paraganglioma (PMID: 19454582). This variant is also referred to as c.242del* in the literature. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Dec 18, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29386252, 19454582, 28944243) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs878854591; hg19: chr11-111959661;