Submissions for variant NM_003002.4(SDHD):c.113G>C (p.Arg38Pro)

dbSNP: rs199901239

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002232273	SCV000640142	uncertain significance	Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 38 of the SDHD protein (p.Arg38Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SDHD-related conditions. ClinVar contains an entry for this variant (Variation ID: 465219). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Ambry Genetics	RCV003159820	SCV003855207	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-02	criteria provided, single submitter	clinical testing	The p.R38P variant (also known as c.113G>C), located in coding exon 2 of the SDHD gene, results from a G to C substitution at nucleotide position 113. This alteration was identified in a gastrointestinal stromal tumor cohort (Indio V et al. Int J Mol Sci, 2018 Mar;19:). The arginine at codon 38 is replaced by proline, 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.
All of Us Research Program, National Institutes of Health	RCV003999151	SCV004845028	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with proline at codon 38 of the SDHD protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with a gastrointestinal stromal tumor (PMID:29510530). 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.