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 2017-09-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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
Invitae RCV000641050 SCV000762668 likely pathogenic Paraganglioma and gastric stromal sarcoma; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2018-11-06 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 reported to segregate with paraganglioma in families (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. Three additional missense substitution at this codon (p.His102Pro, p.His102Arg, p.His102Tyr) has been observed in individuals affected with paragangliomas (PMID: 19454582, 22025150, 22241717). This suggests that the histidine residue is critical for SDHD protein function. 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.
OMIM RCV000007307 SCV000027504 pathogenic Paragangliomas 1 2000-02-04 no assertion criteria provided literature only

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