Submissions for variant NM_003002.4(SDHD):c.342T>A (p.Tyr114Ter) (rs1050032491)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000546525	SCV000645370	pathogenic	Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3	2017-08-07	criteria provided, single submitter	clinical testing	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). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000118	SCV001156553	pathogenic	not specified	2018-10-29	criteria provided, single submitter	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.
Section on Medical Neuroendocrinolgy,National Institutes of Health	RCV000505385	SCV000599543	pathogenic	Hereditary Paraganglioma-Pheochromocytoma Syndromes		no assertion criteria provided	research

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