Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002240202 | SCV001213365 | likely pathogenic | Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3 | 2019-11-25 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine with tyrosine at codon 102 of the SDHD protein (p.His102Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.His102 amino acid residue in SDHD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10657297, 12811540, 19454582, 22025150, 22241717). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with paraganglioma-pheochromocytoma syndrome (PMID: 22241717, Invitae). This variant is not present in population databases (ExAC no frequency). |
| Ambry Genetics | RCV002445259 | SCV002754026 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-02-17 | criteria provided, single submitter | clinical testing | The p.H102Y pathogenic mutation (also known as c.304C>T), located in coding exon 3 of the SDHD gene, results from a C to T substitution at nucleotide position 304. The histidine at codon 102 is replaced by tyrosine, an amino acid with few similar properties. This variant has been reported in multiple individuals with a clinical diagnossis of paraganglioma-pheochromocytoma (PGL/PCC) syndrome (Piccini V et al. Endocr. Relat. Cancer. 2012 Apr;19(2):149-55; Bacca A et al. Head Neck. 2013 Jan;35(1):23-7; Benn DE et al. Endocr. Relat. Cancer. 2015 Aug;22:T91-103). Several other variants at the same codon (p.H102L, p.H102R, p.H102Y, and p.H102P) have been described in individuals with head and neck paraganglioma (Poeppel TD et al J. Clin. Oncol. 2011 Nov;29(33):e812-5; Piccini V et al. Endocr. Relat. Cancer. 2012 Apr;19(2):149-55; Baysal BE et al. Science. 2000 Feb;287(5454):848-51; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94(8):2817-27). Based on internal structural analysis, this variant is anticipated to disrupt a region of known function (Ambry internal data; Sun F et al. Cell. 2005 Jul;121(7):1043-57; Zhou Q et al. Protein Cell. 2011 Jul;2(7):531-42). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |