ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.53dup (p.Leu19fs) (rs886041237)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000349345 SCV000329513 pathogenic not provided 2017-02-22 criteria provided, single submitter clinical testing This duplication of one nucleotide in SDHD is denoted c.53dupC at the cDNA level and p.Leu19SerfsX50 (L19SfsX50) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TCAG[dupC]TCTG. The duplication causes a frameshift which changes a Leucine to a Serine at codon 19, and creates a premature stop codon at position 50 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.53dupC has been reported in the literature in an individual with a carotid body tumor (Papathomas 2015). We consider this variant to be pathogenic.
Ambry Genetics RCV000492278 SCV000581229 pathogenic Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing The c.53dupC pathogenic mutation, located in coding exon 2 of the SDHD gene, results from a duplication of C at nucleotide position 53, causing a translational frameshift with a predicted alternate stop codon (p.L19Sfs*50). This alteration was seen in a patient diagnosed with a paraganglioma at age 26 (Papathomas TG et al. Mod. Pathol., 2015 Jun;28:807-21). 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 RCV001230818 SCV001403315 pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2019-09-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu19Serfs*50) 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 observed in individuals affected with head and neck paraganglioma or paraganglioma-pheochromocytoma (PMID: 25720320, 29386252, 30050099). This variant is also known as c.53insC (p.19fs*68) in the literature. ClinVar contains an entry for this variant (Variation ID: 279889). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in SDHD are known to be pathogenic (PMID: 19454582, 19802898). For these reasons, this variant has been classified as Pathogenic.
Department of Pediatrics,Memorial Sloan Kettering Cancer Center RCV001523821 SCV001478183 pathogenic Pheochromocytoma 2020-12-15 criteria provided, single submitter research
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505366 SCV000599534 likely pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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