Submissions for variant NM_003002.4(SDHD):c.57del (p.Leu20fs) (rs587776649)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482313	SCV000565548	pathogenic	not provided	2016-05-23	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in SDHD is denoted c.57delG at the cDNA level and p.Leu20CysfsX66 (L20CfsX66) at the protein level. The normal sequence, with the base that is deleted in braces, is CTCT[G]TTGC. The deletion causes a frameshift which changes a Leucine to a Cysteine at codon 20, and creates a premature stop codon at position 66 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. SDHD c.57delG has been reported at least once in an individual with a personal history of gastrointestinal stromal tumor (GIST), pheochromocytoma, and multiple paragangliomas (McWhinney 2007, Pasini 2008). Based on the currently available information, we consider this variant to be pathogenic.
Ambry Genetics	RCV000492772	SCV000581225	pathogenic	Hereditary cancer-predisposing syndrome	2015-10-03	criteria provided, single submitter	clinical testing
Invitae	RCV000641042	SCV000762660	pathogenic	Paraganglioma and gastric stromal sarcoma; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3	2017-10-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu20Cysfs*66) in the SDHD gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587776649, ExAC 0.001%). This variant has been reported in an individual affected with gastrointestinal stromal tumor, pheochromocytoma, and multiple paragangliomas (PMID: 17667967). ClinVar contains an entry for this variant (Variation ID: 6917). Loss-of-function variants in SDHD are known to be pathogenic (PMID: 19454582, 19802898). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000007326	SCV000027524	pathogenic	Paraganglioma and gastric stromal sarcoma	2008-01-01	no assertion criteria provided	literature only
Section on Medical Neuroendocrinolgy,National Institutes of Health	RCV000505302	SCV000599532	pathogenic	Hereditary Paraganglioma-Pheochromocytoma Syndromes		no assertion criteria provided	research

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