ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.191_192del (p.Leu64fs) (rs387906358)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481193 SCV000568556 pathogenic not provided 2016-07-25 criteria provided, single submitter clinical testing This deletion of two nucleotides in SDHD is denoted c.191_192delTC at the cDNA level and p.Leu64ProfsX4 (L64PfsX4) at the protein level. The normal sequence, with the bases that are deleted in braces, is TCTC[TC]CACT. The deletion causes a frameshift which changes a Leucine to a Proline at codon 64, and creates a premature stop codon at position 4 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.191_192delTC tracked with disease in a large Australian family with hereditary paraganglioma (Badenhop 2001), and has been reported in multiple individuals with paraganglioma, including those with an apparently sporadic tumor (Burnichon 2009, Neumann 2009, Jafri 2013, Curras-Freixes 2015). We consider this variant to be pathogenic.
Invitae RCV000641035 SCV000762653 pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2017-12-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu64Profs*4) 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 variant has been reported  in the literature in individuals and families affected with paraganglioma, and segregates with disease in at lease one family (PMID: 11391796, 15235042, 19454582, 23902947). ClinVar contains an entry for this variant (Variation ID: 6904). Loss-of-function variants in SDHD are known to be pathogenic (PMID: 19454582, 19802898). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001013655 SCV001174270 pathogenic Hereditary cancer-predisposing syndrome 2018-10-17 criteria provided, single submitter clinical testing The c.191_192delTC variant, located in coding exon 3 of the SDHD gene, results from a deletion of two nucleotides at nucleotide positions 191 to 192, causing a translational frameshift with a predicted alternate stop codon (p.L64Pfs*4). This alteration has been reported in individuals with familial paraganglioma ​(Badenhop RF et al. Genes Chromosomes Cancer. 2001 Jul;31:255-63; Badenhop RF et al. J. Med. Genet. 2004 Jul;41:e99; Cascón A et al. J. Clin. Endocrinol. Metab. 2009 May;94:1701-5). It has also been reported in individuals with apparently sporadic paraganglioma (Amar L et al. J. Clin. Oncol. 2005 Dec;23:8812-8; Currás-Freixes M et al. J. Med. Genet. 2015 Oct;52:647-56). Multiple cohort studies of patients with parangliomas have also identified this variant (Neumann HP et al. Cancer Res. 2009 Apr;69:3650-6; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94:2817-27; Merlo A et al. J. Clin. Endocrinol. Metab. 2013 Oct;98:E1661-6; Jafri M et al. Clin. Endocrinol. (Oxf). 2013 Jun;78:898-906; de Cubas AA et al. Endocr. Relat. Cancer. 2013 Aug;20:477-93; Andrews KA et al. J. Med. Genet. 2018 Jun;55:384-394). 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.
OMIM RCV000007313 SCV000027510 pathogenic Paragangliomas 1 with sensorineural hearing loss 2001-07-01 no assertion criteria provided literature only

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