Submissions for variant NM_003001.5(SDHC):c.7G>A (p.Ala3Thr)

gnomAD frequency: 0.00001  dbSNP: rs748243732

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000462901	SCV000546044	uncertain significance	Gastrointestinal stromal tumor; Paragangliomas 3	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3 of the SDHC protein (p.Ala3Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 407063). 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	RCV002418367	SCV002678662	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-12	criteria provided, single submitter	clinical testing	The p.A3T variant (also known as c.7G>A), located in coding exon 1 of the SDHC gene, results from a G to A substitution at nucleotide position 7. The alanine at codon 3 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV003153608	SCV003842387	uncertain significance	not provided	2022-09-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV003476039	SCV004203075	uncertain significance	Gastrointestinal stromal tumor	2023-06-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000762	SCV004829535	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2023-06-15	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 3 of the SDHC 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 hereditary paranganglioma-pheochromocytoma syndrome (PMID: 29504908). This variant has been identified in 5/282430 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.
PreventionGenetics, part of Exact Sciences	RCV004751531	SCV005367120	uncertain significance	SDHC-related disorder	2024-06-13	no assertion criteria provided	clinical testing	The SDHC c.7G>A variant is predicted to result in the amino acid substitution p.Ala3Thr. To our knowledge, this variant has not been reported in the literature in SDHC associated germline diseases. This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. This variant is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/407063/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.