ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.72+1G>A

dbSNP: rs587782703
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492576 SCV000581207 pathogenic Hereditary cancer-predisposing syndrome 2022-10-19 criteria provided, single submitter clinical testing The c.72+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 1 of the SDHB gene. This alteration has been previously identified in an individual with extra-adrenal paragangliomas (PGL) (Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug; 94(8):2817-27). Two additional alterations affecting the same nucleotide position (c.72+1G>C and c.72+1G>T) have also been described in PGL cohorts (Ricketts CJ et al. Hum. Mutat. 2010 Jan; 31(1):41-51; Benn DE et al. J. Clin. Endocrinol. Metab. 2006 Mar; 91(3):827-36). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV002527067 SCV003523171 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2022-03-09 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 1 of the SDHB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is present in population databases (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with clinical features of SDHB-related conditions (PMID: 16317055, 16472267, 16912137, 17667967, 18419787, 19454582, 20418362, 20459544, 29386252, 30877234). ClinVar contains an entry for this variant (Variation ID: 428927). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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