ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.278A>G (p.Tyr93Cys) (rs142135772)

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Total submissions: 4
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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 2020-01-16 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 variant has been identified in two individuals with 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 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 limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000231432 SCV000287822 uncertain significance Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 93 of the SDHD protein (p.Tyr93Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs142135772, ExAC 0.1%). This variant has been reported in individuals affected with Cowden syndrome (PMID: 25376524). ClinVar contains an entry for this variant (Variation ID: 135197). An experimental study has shown that this missense change does not affect SDHD protein expression, enzymatic activity, or mitochondrial morphology in a cultured neuroblastoma cell line (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 2021-04-30 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in two individuals with breast and endometrial cancer from a cohort of patients with Cowden or Cowden-like syndrome (Mahdi 2014); This variant is associated with the following publications: (PMID: 25376524, 28873162, 15331017, 24728327, 22904323)
ITMI RCV000122009 SCV000086220 not provided not specified 2013-09-19 no assertion provided reference population

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