ClinVar Miner

Submissions for variant NM_003001.5(SDHC):c.224G>A (p.Gly75Asp)

dbSNP: rs786205147
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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 RCV000564191 SCV000675104 pathogenic Hereditary cancer-predisposing syndrome 2020-06-01 criteria provided, single submitter clinical testing The p.G75D pathogenic mutation (also known as c.224G>A), located in coding exon 4 of the SDHC gene, results from a G to A substitution at nucleotide position 224. The glycine at codon 75 is replaced by aspartic acid, an amino acid with similar properties. In a study of 598 unrelated probands diagnosed with head and neck paraganglioma, this pathogenic variant was detected in 2 individuals (Neumann HP et al. Cancer Res. 2009 Apr;69:3650-6). This pathogenic variant has also been detected in an individual with Carney triad (Boikos SA et al. Eur. J. Hum. Genet. 2016 Apr;24:569-73). Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Ambry internal data; Zhou Q et al. Protein Cell. 2011 Jul;2:531-42). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000688261 SCV000815866 likely pathogenic Gastrointestinal stromal tumor; Paragangliomas 3 2021-10-25 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SDHC protein function. ClinVar contains an entry for this variant (Variation ID: 189841). This missense change has been observed in individuals with paraganglioma and condroma (PMID: 19351833, 26173966; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 75 of the SDHC protein (p.Gly75Asp).
Section on Endocrinology and Genetics, National Institutes of Health / The Eunice Kennedy Shriver National Institute of Child Health and Human Development RCV000170332 SCV000222641 likely pathogenic Carney triad no assertion criteria provided clinical testing

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