Submissions for variant NM_003001.5(SDHC):c.98C>T (p.Thr33Met)

gnomAD frequency: 0.00007  dbSNP: rs148566767

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000459835	SCV000546032	uncertain significance	Gastrointestinal stromal tumor; Paragangliomas 3	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 33 of the SDHC protein (p.Thr33Met). This variant is present in population databases (rs148566767, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SDHC-related conditions. ClinVar contains an entry for this variant (Variation ID: 407054). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	RCV000561060	SCV000675095	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-28	criteria provided, single submitter	clinical testing	The p.T33M variant (also known as c.98C>T), located in coding exon 3 of the SDHC gene, results from a C to T substitution at nucleotide position 98. The threonine at codon 33 is replaced by methionine, an amino acid with similar properties. This amino acid position is 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759344	SCV000888621	uncertain significance	not provided	2020-01-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000759344	SCV001872794	uncertain significance	not provided	2023-09-22	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; Identified in an individual with bilateral renal cell carcinoma in published literature (PMID: 35441217); This variant is associated with the following publications: (PMID: 35441217)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003401466	SCV004122809	uncertain significance	not specified	2023-10-12	criteria provided, single submitter	clinical testing	Variant summary: SDHC c.98C>T (p.Thr33Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251480 control chromosomes. The observed variant frequency is approximately 330.84 fold of the estimated maximal expected allele frequency for a pathogenic variant in SDHC causing Hereditary Paraganglioma-Pheochromocytoma Syndrome phenotype (1.6e-07), suggesting that the variant may be benign. c.98C>T has been reported in the literature in individuals affected with renal cell carcinoma or an unspecified cancer type, without evidence of causality (e.g. Kim_2018, Yngvadottir_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Paraganglioma-Pheochromocytoma Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30583724, 35441217). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Baylor Genetics	RCV003476037	SCV004203052	uncertain significance	Gastrointestinal stromal tumor	2023-10-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003507279	SCV004362291	uncertain significance	Paragangliomas 3	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 33 of the SDHC 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 SDHC-related disorders in the literature. This variant has been identified in 14/282888 chromosomes 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.
All of Us Research Program, National Institutes of Health	RCV004000759	SCV004815848	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 33 of the SDHC 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 been reported in an individual affected with clear cell renal carcinoma (PMID: 35441217). This variant has been identified in 14/282888 chromosomes 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000759344	SCV005408524	uncertain significance	not provided	2024-06-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005049554	SCV005680750	uncertain significance	Gastrointestinal stromal tumor; Carney-Stratakis syndrome; Paragangliomas 3	2024-05-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003424016	SCV004117262	uncertain significance	SDHC-related disorder	2024-05-16	no assertion criteria provided	clinical testing	The SDHC c.98C>T variant is predicted to result in the amino acid substitution p.Thr33Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD. It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/407054/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.