rs878854589

Variant names:

• chr11-112086916-T-TC
• rs878854589
• NM_003002.4:c.10dupC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003002.4(SDHD):​c.10dupC​(p.Leu4ProfsTer65) 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. L4L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHD NM_003002.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -1.25
• 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]

ENSG00000255292 (HGNC:):

TIMM8B (HGNC:11818): (translocase of inner mitochondrial membrane 8 homolog B) This gene encodes a member of a well-conserved family of proteins with similarity to yeast Tim mitochondrial import proteins. This gene is encoded by a nuclear gene and is transported into the intermembrane space of the mitochondrion. When formed into complexes, these proteins guide membrane-spanning proteins across the mitochondrial intermembrane space before they are added into the mitochondrial inner membrane. This gene is adjacent to succinate dehydrogenase, subunit D (SDHD), in which mutations have been found in affected members of families with hereditary paraganglioma.[provided by RefSeq, Aug 2009]

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 125 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-112086916-T-TC is Pathogenic according to our data. Variant chr11-112086916-T-TC is described in CliVar as Pathogenic. Clinvar id is 239460.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-112086916-T-TC is described in CliVar as Pathogenic. Clinvar id is 239460.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-112086916-T-TC is described in CliVar as Pathogenic. Clinvar id is 239460.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-112086916-T-TC is described in CliVar as Pathogenic. Clinvar id is 239460.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-112086916-T-TC is described in CliVar as Pathogenic. Clinvar id is 239460.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-112086916-T-TC is described in CliVar as Pathogenic. Clinvar id is 239460.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-112086916-T-TC is described in CliVar as Pathogenic. Clinvar id is 239460.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-112086916-T-TC is described in CliVar as Pathogenic. Clinvar id is 239460.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-112086916-T-TC is described in CliVar as Pathogenic. Clinvar id is 239460.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-112086916-T-TC is described in CliVar as Pathogenic. Clinvar id is 239460.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-112086916-T-TC is described in CliVar as Pathogenic. Clinvar id is 239460.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHD	NM_003002.4	c.10dupC	p.Leu4ProfsTer65	frameshift_variant	Exon 1 of 4	ENST00000375549.8	NP_002993.1
TIMM8B	NM_012459.4	c.-194dupG		upstream_gene_variant		ENST00000504148.3	NP_036591.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.10dupC	p.Leu4ProfsTer65	frameshift_variant	Exon 1 of 4	1	NM_003002.4	ENSP00000364699.3
ENSG00000255292	ENST00000532699.1	n.10dupC		non_coding_transcript_exon_variant	Exon 1 of 6	3		ENSP00000456434.1
TIMM8B	ENST00000504148.3	c.-194dupG		upstream_gene_variant		1	NM_012459.4	ENSP00000422122.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 01, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change inserts 1 nucleotide in exon 1 of the SDHD mRNA (c.10dupC), causing a frameshift at codon 4. This creates a premature translational stop signal (p.Leu4Profs*65) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in SDHD are known to be pathogenic (PMID: 19802898, 19454582). For these reasons, this variant has been classified as Pathogenic. -

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

Jan 01, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change inserts 1 nucleotide in exon 1 of the SDHD mRNA (c.10dupC), causing a frameshift at codon 4. This creates a premature translational stop signal (p.Leu4Profs*65) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in SDHD are known to be pathogenic (PMID: 19802898, 19454582). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs878854589; hg19: chr11-111957640;