Submissions for variant NM_003002.4(SDHD):c.112C>T (p.Arg38Ter)

dbSNP: rs80338843

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002228000	SCV000287812	pathogenic	Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3	2023-08-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6893). This premature translational stop signal has been observed in individual(s) with paraganglioma and pheochromocytoma (PMID: 10657297, 11156372, 11897817, 12000816, 15328326, 19454582, 19825962, 21348866, 26269449). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg38*) 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).
GeneDx	RCV000486967	SCV000568552	pathogenic	not provided	2023-08-18	criteria provided, single submitter	clinical testing	Nonsense 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: 10657297, 12000816, 19825962, 12811540, 21348866, 12351569, 26273102, 12205103, 8981955, 27867439, 27700540, 33219105, 25525159, 11156372, 25791839, 17563904, 12364472, 22517557, 20418362, 11897817, 11391798, 15328326, 19454582, 26269449, 15066320, 22566157, 28748451, 27073498, 32561571, 34750850)
Ambry Genetics	RCV000492087	SCV000581231	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-31	criteria provided, single submitter	clinical testing	The p.R38* pathogenic mutation (also known as c.112C>T), located in coding exon 2 of the SDHD gene, results from a C to T substitution at nucleotide position 112. This changes the amino acid from an arginine to a stop codon within coding exon 2. This mutation has been reported in multiple individuals diagnosed with pheochromocytoma(s) and/or extra-adrenal paraganglioma(s) (Baysal BE et al. Science 2000 Feb;287(5454):848-51; Gimm O et al. Cancer Res. 2000 Dec;60(24):6822-5; Baysal BE et al. J. Med. Genet. 2002 Mar;39(3):178-83; Neumann HP et al. N. Engl. J. Med. 2002 May;346(19):1459-66; Erlic Z et al. Clin. Cancer Res. 2009 Oct;15(20):6378-85; Lodish MB et al. Endocr. Relat. Cancer 2010 Sep;17(3):581-8). One study identified this mutation in an unaffected individual as well as in his two children who were both affected with paragangliomas (Fish JH et al. Head Neck 2007 Sep;29(9):864-73). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000020518	SCV000731539	pathogenic	Hereditary pheochromocytoma-paraganglioma	2017-03-01	criteria provided, single submitter	clinical testing	The p.Arg38X variant in SDHD has been reported in at least 9 individuals with SD HD-associated cancers, segregated with disease in at least 10 affected relatives from multiple families (Gimm 2000, Baysal 2000;2002,Neumann 2004, Erlic 2009, B urnichon 2009, Hensen 2012, ClinVar ID#6893), and was absent from large populati on studies. This nonsense variant leads to a premature termination codon at posi tion 38, which is predicted to lead to a truncated or absent protein. Heterozygo us loss of function of the SDHD gene is an established disease mechanism in indi viduals with hereditary paragangliomas and pheochromocytomas. In summary, this v ariant meets criteria to be classified as pathogenic for hereditary paragangliom as and pheochromocytomas in an autosomal dominant manner based upon segregation studies and the predicted impact to the protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020518	SCV002500781	pathogenic	Hereditary pheochromocytoma-paraganglioma	2022-03-30	criteria provided, single submitter	clinical testing	Variant summary: SDHD c.112C>T (p.Arg38X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251472 control chromosomes (gnomAD). c.112C>T has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome and was shown to co-segregate with disease within families (e.g. Baysal_2000, Neumann_2002, Erlic_2009, Ding_2019). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000020518	SCV002761360	pathogenic	Hereditary pheochromocytoma-paraganglioma	2019-08-15	criteria provided, single submitter	clinical testing
OMIM	RCV000007296	SCV000027492	pathogenic	Paragangliomas 1	2002-05-09	no assertion criteria provided	literature only
OMIM	RCV000007297	SCV000027493	pathogenic	Pheochromocytoma	2002-05-09	no assertion criteria provided	literature only
GeneReviews	RCV000020518	SCV000040975	not provided	Hereditary pheochromocytoma-paraganglioma		no assertion provided	literature only
Section on Medical Neuroendocrinolgy, National Institutes of Health	RCV000020518	SCV000599535	pathogenic	Hereditary pheochromocytoma-paraganglioma		no assertion criteria provided	research