ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.209G>A (p.Arg70Lys) (rs755047928)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000230516 SCV000287816 uncertain significance Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2020-07-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 70 of the SDHD protein (p.Arg70Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs755047928, ExAC 0.001%). This variant has not been reported in the literature in individuals with SDHD-related disease. ClinVar contains an entry for this variant (Variation ID: 239463). 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. The observation of one or more missense substitutions at this codon (p.Arg70Thr, p.Arg70Met, p.Arg70Ser, and p.Arg70Gly) in affected individuals suggests that this may be a clinically significant residue (PMID: 1945482, 19258401, 11391798, 22566194). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV001014431 SCV001175135 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-27 criteria provided, single submitter clinical testing The p.R70K variant (also known as c.209G>A), located in coding exon 3 of the SDHD gene, results from a G to A substitution at nucleotide position 209. The arginine at codon 70 is replaced by lysine, an amino acid with highly similar properties. A different alteration at this position, p.R70M, has been reported in the literature in multiple individuals diagnosed with paragangliomas (Burnichon N et al. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27; Haller F et al. Endocr. Relat. Cancer, 2014 Aug;21:567-77​; Persu A et al. J. Hypertens., 2008 Jul;26:1395-401; van Nederveen FH et al. Lancet Oncol., 2009 Aug;10:764-71). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505342 SCV000599539 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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