Submissions for variant NM_003001.5(SDHC):c.295T>C (p.Tyr99His)

gnomAD frequency: 0.00001  dbSNP: rs760678574

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231142	SCV000287799	uncertain significance	Gastrointestinal stromal tumor; Paragangliomas 3	2024-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 99 of the SDHC protein (p.Tyr99His). This variant is present in population databases (rs760678574, gnomAD 0.002%). 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: 239453). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The histidine 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.
GeneDx	RCV000482240	SCV000570669	uncertain significance	not provided	2016-06-16	criteria provided, single submitter	clinical testing	This variant is denoted SDHC c.295T>C at the cDNA level, p.Tyr99His (Y99H) at the protein level, and results in the change of a Tyrosine to a Histidine (TAT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. SDHC Tyr99His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Tyrosine and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. SDHC Tyr99His occurs at a position that is not conserved and is located in the mitochondrial intermembrane domain (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether SDHC Tyr99His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482240	SCV001134813	uncertain significance	not provided	2020-08-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002256145	SCV002527105	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-22	criteria provided, single submitter	curation
Ambry Genetics	RCV002256145	SCV002749122	likely benign	Hereditary cancer-predisposing syndrome	2023-10-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Baylor Genetics	RCV003475064	SCV004203050	uncertain significance	Gastrointestinal stromal tumor	2024-02-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003507270	SCV004362294	uncertain significance	Paragangliomas 3	2022-11-06	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 99 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 not been reported in individuals affected with SDHC-related disorders in the literature. This variant has been identified in 2/280304 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	RCV003998863	SCV004818868	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 99 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 not been reported in individuals affected with SDHC-related disorders in the literature. This variant has been identified in 2/280304 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.