Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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. |
Labcorp Genetics |
RCV002512870 | SCV000762653 | pathogenic | Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3 | 2022-07-04 | 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: 6904). This premature translational stop signal has been observed in individual(s) with paraganglioma (PMID: 11391796, 15235042, 19454582, 23902947). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). 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. Loss-of-function variants in SDHD are known to be pathogenic (PMID: 19454582, 19802898). |
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 | RCV004018581 | SCV000027510 | pathogenic | Paragangliomas 1 | 2001-07-01 | no assertion criteria provided | literature only |