Submissions for variant NM_003002.4(SDHD):c.18G>T (p.Arg6Ser)

dbSNP: rs200895313

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002534431	SCV000834199	uncertain significance	Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3	2022-09-20	criteria provided, single submitter	clinical testing	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 not expected to disrupt 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. ClinVar contains an entry for this variant (Variation ID: 581402). This variant has not been reported in the literature in individuals affected with SDHD-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 6 of the SDHD protein (p.Arg6Ser).
All of Us Research Program, National Institutes of Health	RCV003999764	SCV004845020	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with serine at codon 6 of the SDHD protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV004659184	SCV005161261	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-24	criteria provided, single submitter	clinical testing	The p.R6S variant (also known as c.18G>T), located in coding exon 1 of the SDHD gene, results from a G to T substitution at nucleotide position 18. The arginine at codon 6 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.