ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.305A>T (p.His102Leu) (rs104894302)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000566289 SCV000664577 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-09 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Well-characterized mutation at same position;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000641050 SCV000762668 pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces histidine with leucine at codon 102 of the SDHD protein (p.His102Leu). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with paragangliomas (Invitae). It has also been observed to segregate with disease in related individuals (PMID: 10657297, 12811540). ClinVar contains an entry for this variant (Variation ID: 6898). 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 disrupts the p.His102 amino acid residue in SDHD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22241717, Invitae, external communication). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000007307 SCV000027504 pathogenic Paragangliomas 1 2000-02-04 no assertion criteria provided literature only

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