Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002524414 | SCV000762655 | pathogenic | Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3 | 2024-01-11 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 2 of the SDHD 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 SDHD 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 individual(s) with SDHD-related conditions (PMID: 12114404, 12509798, 18551016, 19075037, 22566194, 29545045, 30050099, 30877234). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 438434). 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. |
| Ambry Genetics | RCV002413385 | SCV002715773 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-05-06 | criteria provided, single submitter | clinical testing | The c.170-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 3 of the SDHD gene. This alteration has been identified in numerous patients from multiple ethnic groups with unilateral or bilateral carotid body tumors, both with and without a family history of pheochromocytomas and/or paragangliomas (Dannenberg H et al. Clin. Cancer Res. 2002 Jul;8:2061-6; Persu A et al. J. Hypertens. 2008 Jul;26:1395-401; Renard L et al. Head Neck. 2003 Feb;25:146-51; Zuo Y et al. Urology. 2018 06;116:63-67; Santi R et al. Anticancer Res. 2017 02;37:805-812; Piccini V et al. Endocr. Relat. Cancer. 2012 Apr;19:149-55; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94:2817-27; Astrom K et al. Hum. Genet. 2003 Aug;113:228-37; Benn DE et al. J. Clin. Endocrinol. Metab. 2006 Mar;91:827-36). This alteration was also identified in a patient with a glomus tumor (Mannelli M et al. Ann. N. Y. Acad. Sci. 2006 Aug;1073:183-9), a patient with bilateral carotid body tumors and a primary mediastinal paraganglioma (Ghayee HK et al. Endocr. Relat. Cancer. 2009 Mar;16:291-9;), and patients with cervical paragangliomas (Bauters C et al. J. Med. Genet. 2003 Jun;40:e75). Of note, this alteration is also designated as IVS2-1G>T in the published literature. 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 likely pathogenic. |
| Section on Medical Neuroendocrinolgy, |
RCV000505295 | SCV000599538 | pathogenic | Hereditary pheochromocytoma-paraganglioma | no assertion criteria provided | research |