ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.440A>G (p.Tyr147Cys) (rs774568101)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000469133 SCV000554000 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 147 of the SDHB protein (p.Tyr147Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs774568101, ExAC 0.04%), including at least one homozygous individual. This variant has been reported in an individual affected with pheochromocytoma (PMID: 28229225). This variant has also been observed in an individual with a family history of renal cancer (Invitae). However, in that individual a pathogenic allele was also identified in SDHB, which suggests that this c.440A>G variant was not the primary cause of disease in the family. ClinVar contains an entry for this variant (Variation ID: 412466). Experimental studies have shown that this missense change results in altered SDHB subcellular localization, and significant reduction of SDH activity in vitro (PMID: 28229225). 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 RCV000492611 SCV000581187 uncertain significance Hereditary cancer-predisposing syndrome 2020-05-06 criteria provided, single submitter clinical testing The p.Y147C variant (also known as c.440A>G), located in coding exon 5 of the SDHB gene, results from an A to G substitution at nucleotide position 440. The tyrosine at codon 147 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was detected in one individual, diagnosed with a sporadic pheochromocytoma at age 75, whose tumor demonstrated presence of the SDHB protein. Further in vivo functional analysis of Y147C demonstrated reduced mitochondrial localization and reduced SDH activity compared to wild type (Maignan A et al. Langenbecks Arch Surg. 2017 Aug;402:787-798). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear.
Mendelics RCV000708786 SCV000837735 uncertain significance Cowden syndrome 2018-07-02 criteria provided, single submitter clinical testing
Baylor Genetics RCV001294088 SCV001482894 uncertain significance Pheochromocytoma 2019-08-24 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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