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

Total submissions: 6

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	The c.57delG pathogenic mutation, located in coding exon 2 of the SDHD gene, results from a deletion of one nucleotide at nucleotide position 57, causing a translational frameshift with a predicted alternate stop codon. This alteration has been previously identified in individuals with paraganglioma(s) and gastrointestinal stromal tumor (GIST) (<span style="background-color:initial">Pasini B et al. Eur. J. Hum. Genet. 2008 Jan;16(1):79-88; Lodish MB et al. Endocr. Relat. Cancer 2010 Sep;17(3):581-8; Wang YM et al. World J. Gastroenterol. 2015 Feb;21(8):2303-14).<span style="background-color:initial"> 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.
Invitae	RCV000641042	SCV000762660	pathogenic	Carney-Stratakis syndrome; 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.
Integrated Genetics/Laboratory Corporation of America	RCV000505302	SCV001337824	pathogenic	Hereditary Paraganglioma-Pheochromocytoma Syndromes	2020-01-17	criteria provided, single submitter	clinical testing	Variant summary: SDHD c.57delG (p.Leu20CysfsX66) 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 251434 control chromosomes. c.57delG has been reported in the literature in individuals from at-least one family affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome/Carney-Stratakis dyad (McWhinney_2007, Pasini_2008, Ghayee_2009, Lodish_2010). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 citing overlapping evidence utilized in the context of this evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000007326	SCV000027524	pathogenic	Carney-Stratakis syndrome	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