ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.112C>T (p.Arg38Ter) (rs80338843)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000227867 SCV000287812 pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2020-08-16 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). This particular truncation has been reported in the literature in several individuals and families with paraganglioma and pheochromocytoma (PMID: 10657297, 12000816, 19825962, 21348866, 15328326, 11897817, 11156372, 19454582, 26269449). ClinVar contains an entry for this variant (Variation ID: 6893). Loss-of-function variants in SDHD are known to be pathogenic (PMID: 19454582, 19802898). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000486967 SCV000568552 pathogenic not provided 2018-09-28 criteria provided, single submitter clinical testing This variant is denoted SDHD c.112C>T at the cDNA level and p.Arg38Ter (R38X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. SDHD Arg38Ter has been reported in association with both familial and apparently sporadic paragangliomas and pheochromocytomas (Baysal 2000, Neumann 2004, Fish 2007, Burnichon 2009, Zheng 2012). This variant is considered pathogenic.
Ambry Genetics RCV000492087 SCV000581231 pathogenic Hereditary cancer-predisposing syndrome 2017-10-27 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, Partners HealthCare Personalized Medicine RCV000020518 SCV000731539 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 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.
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 pathologic Hereditary Paraganglioma-Pheochromocytoma Syndromes 2012-08-30 no assertion criteria provided curation Converted during submission to Pathogenic.
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000020518 SCV000599535 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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