ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.412G>A (p.Gly138Arg) (rs786203932)

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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 RCV000167450 SCV000218306 likely pathogenic Hereditary cancer-predisposing syndrome 2018-12-21 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Structural Evidence
GeneDx RCV000478572 SCV000572139 likely pathogenic not provided 2016-10-31 criteria provided, single submitter clinical testing This variant is denoted SDHD c.412G>A at the cDNA level, p.Gly138Arg (G138R) at the protein level, and results in the change of a Glycine to an Arginine (GGG>AGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. SDHD Gly138Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. SDHD Gly138Arg occurs at a position that is conserved across species and is located in the helical transmembrane region (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider SDHD Gly138Arg to be a likely pathogenic variant.
Invitae RCV001045734 SCV001209605 uncertain significance Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2019-10-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 138 of the SDHD protein (p.Gly138Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 187700). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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