ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.337_340del (p.Asp113fs) (rs587776648)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485947 SCV000565549 pathogenic not provided 2018-04-16 criteria provided, single submitter clinical testing This deletion of four nucleotides in SDHD is denoted c.337_340delGACT at the cDNA level and p.Asp113MetfsX21 (D113MfsX21) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TACT[delGACT]ATGT. The deletion causes a frameshift, which changes an Aspartic Acid to a Methionine at codon 113, and creates a premature stop codon at position 21 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation as the last 47 amino acids are no longer translated. The disrupted region includes the helical transmembrane topological domain and the ubiquinone binding site (UniProt). This variant, also known as SDHD c.334_337delACTG, is a recurrent variant that has been reported in many individuals with early-onset and/or multiple paragangliomas/pheochromocytomas, and has been shown to track with disease in several families (Cascon 2002, Velasco 2005, Benn 2006, Lima 2007, Hermsen 2010, Lefebvre 2012). Paragangliomas from individuals carrying this variant have demonstrated loss of SDHB by IHC, and functional assays have shown that this variant results in a significant reduction of SDH enzyme activity and SDHB protein expression (Rapizzi 2012, Pai 2014). We consider this variant to be pathogenic. Of note, variants in the SDHD gene exhibit a parent-of-origin effect and, if shown to be pathogenic, typically cause symptoms only if inherited from the father.
Invitae RCV000811472 SCV000951739 pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2019-09-19 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SDHD gene (p.Asp113Metfs*21). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acids of the SDHD protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with paragangliomas and/or pheochromocytomas and has also been found to segregate with disease in several families (PMID: 12111639, 27539324,22517554, 21348866, 17848412). This variant is also referred to as 13732delGACT in the literature. ClinVar contains an entry for this variant (Variation ID: 6912). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000007321 SCV000027519 pathogenic Paragangliomas 1 2002-08-01 no assertion criteria provided literature only

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