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

dbSNP: rs786205147

Total submissions: 3

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000688261	SCV000815866	likely pathogenic	Gastrointestinal stromal tumor; Paragangliomas 3	2021-10-25	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with paraganglioma and condroma (PMID: 19351833, 26173966; Invitae). ClinVar contains an entry for this variant (Variation ID: 189841). 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. 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. 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