ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.278A>G (p.Tyr93Cys)

gnomAD frequency: 0.00049  dbSNP: rs142135772
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130895 SCV000185804 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-29 criteria provided, single submitter clinical testing The p.Y93C variant (also known as c.278A>G), located in coding exon 3 of the SDHD gene, results from an A to G substitution at nucleotide position 278. The tyrosine at codon 93 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been observed in at least one individual with a personal history of pheochromocytoma (Ambry internal data). This alteration was detected in two African American breast and endometrial cancer patients out of 371 patients with Cowden or Cowden-like syndrome (Mahdi H et al. Cancer, 2015 Mar;121:688-96). This alteration has also been observed in a neuroblastoma cell line and was not found in 135 controls; it is located in one of the transmembrane helices of the SDHD protein (De Preter K et al. BMC Cancer, 2004 Aug;4:55). This variant was identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS One, 2014 Apr;9:e94554). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae RCV002228625 SCV000287822 uncertain significance Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3 2024-01-17 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 93 of the SDHD protein (p.Tyr93Cys). This variant is present in population databases (rs142135772, gnomAD 0.1%). This missense change has been observed in individual(s) with SDHD-related conditions (PMID: 25376524, 34906457). ClinVar contains an entry for this variant (Variation ID: 135197). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHD protein function. Experimental studies have shown that this missense change does not substantially affect SDHD function (PMID: 15331017). 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 RCV001546458 SCV001765979 uncertain significance not provided 2023-06-14 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as Y37C; This variant is associated with the following publications: (PMID: 22904323, 24728327, 15331017, 28873162, 25376524, 34906457)
Genetic Services Laboratory, University of Chicago RCV000122009 SCV002069419 uncertain significance not specified 2019-07-01 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV001546458 SCV003819254 uncertain significance not provided 2021-09-08 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003398736 SCV004121154 uncertain significance SDHD-related condition 2022-09-15 criteria provided, single submitter clinical testing The SDHD c.278A>G variant is predicted to result in the amino acid substitution p.Tyr93Cys. This variant was reported in two individuals with Cowden or Cowden-like syndrome (Mahdi et al 2015. PubMed ID: 25376524). The c.278A>G variant was also reported in 2 cases from a large cohort of individuals with pheochromocytomas and paragangliomas and interpreted as uncertain (Supp. Table 2 in Garrett A et al 2021. PubMed ID: 34906457).This variant is reported in 0.12% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-111959699-A-G) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135197). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics RCV003474733 SCV004203089 uncertain significance Mitochondrial complex 2 deficiency, nuclear type 3 2023-10-16 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001546458 SCV004220345 benign not provided 2023-06-28 criteria provided, single submitter clinical testing
ITMI RCV000122009 SCV000086220 not provided not specified 2013-09-19 no assertion provided reference population

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