chr11-112094832-T-A

Variant names:

• chr11-112094832-T-A
• rs1050032491
• NM_003002.4:c.342T>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_003002.4(SDHD):​c.342T>A​(p.Tyr114*) variant causes a stop gained 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 (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SDHD NM_003002.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.546

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 14 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 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-112094832-T-A is Pathogenic according to our data. Variant chr11-112094832-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 438437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112094832-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHD	NM_003002.4	c.342T>A	p.Tyr114*	stop_gained	Exon 4 of 4	ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.342T>A	p.Tyr114*	stop_gained	Exon 4 of 4	1	NM_003002.4	ENSP00000364699.3
ENSG00000255292	ENST00000532699.1	n.314+5821T>A		intron_variant	Intron 3 of 5	3		ENSP00000456434.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.85e-7 AC: 1 AN: 1459690 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Pathogenic:1

Oct 29, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SDHD c.342T>A; p.Tyr114Ter variant is reported in the literature in multiple individuals affected with paragangliomas (Andrews 2018, Timmers 2008). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 438437), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the SDHD gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein missing the last 46 amino acids. Based on available information, the p.Tyr114Ter variant is considered to be pathogenic. References: Andrews KA et al. Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. J Med Genet. 2018 Jun;55(6):384-394. Timmers HJ et al. Mutations associated with succinate dehydrogenase D-related malignant paragangliomas. Clin Endocrinol (Oxf). 2008 Apr;68(4):561-6. -

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

Aug 06, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

While no functional studies have been performed to test the effects of this particular variant on SDHD protein function or stability, it deletes 46 C-terminal amino acid residues from the SDHD protein. A founder mutation (p.Leu139Pro) has been reported in this region (PMID: 21348866, 11391798), indicating that the C-terminal amino acid residues may be critical for SDHD function. In summary, this is a rare truncating variant that is expected to disrupt 46 C-terminal amino acids of the SDHD protein, including a region shown to be critical for SDHD protein function. In addition, this variant is absent in the population, and has been reported in an affected individual. For these reasons, this variant has been classified as Pathogenic. This sequence change results in a premature translational stop signal in the last exon of the SDHD mRNA at codon 114 (p.Tyr114*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 46 amino acids of the SDHD protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with SDHD-related malignant paragangliomas (PMID: 17973943). -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 05, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y114* pathogenic mutation (also known as c.342T>A), located in coding exon 4 of the SDHD gene, results from a T to A substitution at nucleotide position 342. This changes the amino acid from a tyrosine to a stop codon within coding exon 4. This alteration occurs at the 3' terminus of theSDHD gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 46 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been reported in multiple individuals with paragangliomas (Timmers HJ et al. Clin Endocrinol (Oxf), 2008 Apr;68:561-6; Daniel E et al. Eur J Endocrinol, 2016 Dec;175:561-570; Andrews KA et al. J Med Genet, 2018 06;55:384-394).(McCrary HC et al. JAMA Otolaryngol Head Neck Surg, 2019 07;145:641-646; Greenberg SE et al. Genet Med, 2020 12;22:2101-2107). Other truncating alterations downstream have been observed in individuals with a personal and/or family history that is consistent with SDHD-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

-

Section on Medical Neuroendocrinolgy, National Institutes of Health

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Benign	0.10
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.37	T;T
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-0.41	T
PROVEAN	Benign	-0.41	N;D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.27	T;D
Vest4		0.59
MutPred		0.66		Loss of stability (P = 0.0039);.;
MVP		0.83
ClinPred		0.63	D
GERP RS		-3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1050032491; hg19: chr11-111965556;