ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.304C>A (p.His102Asn) (rs786202403)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165195 SCV000215907 likely pathogenic Hereditary cancer-predisposing syndrome 2014-07-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000705016 SCV000833994 uncertain significance Paraganglioma and gastric stromal sarcoma; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2018-06-08 criteria provided, single submitter clinical testing This sequence change replaces histidine with asparagine at codon 102 of the SDHD protein (p.His102Asn). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SDHD-related disease. ClinVar contains an entry for this variant (Variation ID: 185719). 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. A different missense substitution at this codon (p.His102Leu) has been determined to be clinically significant (PMID: 10657297, 12811540). Three other missense substitutions at this codon (p.His102Pro, p.His102Arg, p.His102Tyr) have 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 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.

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