ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.148C>G (p.His50Asp) (rs779249550)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497964 SCV000589392 likely pathogenic not provided 2017-05-19 criteria provided, single submitter clinical testing The H50D variant has previously been reported in at least one individual with bilateral carotid body paragangliomas (Kung and Oh, 2011). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The H50D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on currently available evidence, H50D is a strong candidate for a pathogenic variant. However, the possibility it could be a rare benign variant cannot be excluded.
Ambry Genetics RCV000569506 SCV000664535 likely pathogenic Hereditary cancer-predisposing syndrome 2017-01-12 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,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000641047 SCV000762665 uncertain significance Paraganglioma and gastric stromal sarcoma; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2017-12-24 criteria provided, single submitter clinical testing This sequence change replaces histidine with aspartic acid at codon 50 of the SDHD protein (p.His50Asp). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with paraganglioma (Invitae). ClinVar contains an entry for this variant (Variation ID: 431847). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505346 SCV000599536 uncertain significance Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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