ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.286+1G>A (rs786201063)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162475 SCV000212847 pathogenic Hereditary cancer-predisposing syndrome 2019-05-10 criteria provided, single submitter clinical testing The c.286+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 3 of the SDHB gene. This pathogenic variant has been reported in multiple unrelated individuals diagnosed with paragangliomas/pheochromocytomas (Brouwers FM et al. J. Clin. Endocrinol. Metab. 2006 Nov;91:4505-9; Timmers HJ et al. J. Clin. Endocrinol. Metab. 2007 Mar;92:779-86; Isobe K et al. Horm. Res. 2007 Feb;68:68-71; Pandit R et al. Eur. J. Endocrinol. 2016 Oct;175:311-23). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Invitae RCV000633969 SCV000755242 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-10-28 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 of the SDHB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with paraganglioma (PMID: 27539324, 16912137) and pheochromocytoma (PMID: 17308434). This variant is also known as IVS3+1 G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 183757). 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001541605 SCV001759624 pathogenic not provided 2021-04-15 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31492822, 17102085, 29623478, 19802898, 19454582, 28152038, 17200167, 25683602, 22517557, 28374168, 26960314, 27539324, 16912137, 17308434, 25525159)
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505373 SCV000599491 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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