Submissions for variant NM_003002.4(SDHD):c.13T>A (p.Trp5Arg)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002389250	SCV002700765	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-18	criteria provided, single submitter	clinical testing	The p.W5R variant (also known as c.13T>A), located in coding exon 1 of the SDHD gene, results from a T to A substitution at nucleotide position 13. The tryptophan at codon 5 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV002509839	SCV002818597	uncertain significance	not provided	2022-07-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV003774307	SCV004588365	uncertain significance	Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3	2023-05-15	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 1771773). 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHD protein function. 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 tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 5 of the SDHD protein (p.Trp5Arg).