Submissions for variant NM_003001.5(SDHC):c.377A>G (p.Tyr126Cys)

gnomAD frequency: 0.00003  dbSNP: rs898854295

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492617	SCV000581216	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-12	criteria provided, single submitter	clinical testing	The p.Y126C variant (also known as c.377A>G), located in coding exon 5 of the SDHC gene, results from an A to G substitution at nucleotide position 377. The tyrosine at codon 126 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals with paragangliomas (Ambry internal data; Lozano Sánchez et al. Angiología. 2010;62(6):214-218; Sen I et al. J Vasc Surg, 2020 May;71:1602-1612.e2; Williams ST et al. Clin Endocrinol (Oxf), 2022 Apr;96:499-512). Based on internal structural analysis, the tyrosine is located near the hemi-binding center and is part of the SQR domain in the SDHC protein; this variant is predicted to destabilize protein structure more than known remote pathogenic variants (Sun F et al. Cell. 2005 Jul;121:1043-57). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000523379	SCV000619404	likely pathogenic	not provided	2023-03-22	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; Also known as p.Y97C; This variant is associated with the following publications: (PMID: 34558728, 29305721, 15989954, 36672771)
Invitae	RCV000551177	SCV000641438	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 3	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 126 of the SDHC protein (p.Tyr126Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paragangliomas (Invitae). ClinVar contains an entry for this variant (Variation ID: 428933). 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) performed at Invitae indicates that this missense variant is expected to disrupt SDHC protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV002286411	SCV002576447	likely pathogenic	Paragangliomas 3	2022-08-29	criteria provided, single submitter	clinical testing	Criteria applied: PM2_SUP,PM1,PS4_MOD,PP3
PreventionGenetics, part of Exact Sciences	RCV003419827	SCV004109276	likely pathogenic	SDHC-related condition	2023-09-27	criteria provided, single submitter	clinical testing	The SDHC c.377A>G variant is predicted to result in the amino acid substitution p.Tyr126Cys. This variant has been reported in five unrelated individuals with head and neck paraganglioma (Lozano Sánchez et al. 2010. Angiologia. 62(6): 214-18. https://doi.org/10.1016/S0003-3170(10)70051-1; Table S1, Verginelli et al. 2018. PubMed ID: 29305721; Supplement, Sen et al. 2020. PubMed ID: 32035780; Tables 3 and S3, Williams et al. 2022. PubMed ID: 34558728). It has also been reported as a likely pathogenic, paternally-inherited secondary finding in a pediatric individual with a neurodevelopmental indication (Table 1, Halfmeyer et al. 2022. PubMed ID: 36672771). This variant is predicted to be protein destabilizing (Williams et al. 2022. PubMed ID: 34558728). This variant has not been reported in a large population database (https://gnomad.broadinstitute.org/), indicating this variant is rare. This variant has been reported in ClinVar as likely pathogenic and pathogenic by outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/428933/). This variant is interpreted as likely pathogenic.
Baylor Genetics	RCV003476182	SCV004203070	likely pathogenic	Gastrointestinal stromal tumor	2023-07-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV002286411	SCV004362297	likely pathogenic	Paragangliomas 3	2023-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 126 of the SDHC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with paraganglioma (PMID: 19245779, 29305721, 32035780, 34558728). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Section on Medical Neuroendocrinolgy, National Institutes of Health	RCV000505370	SCV000599554	pathogenic	Hereditary pheochromocytoma-paraganglioma		no assertion criteria provided	research