ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.274G>T (p.Asp92Tyr)

gnomAD frequency: 0.00001  dbSNP: rs80338845
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002512869 SCV000287820 pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3 2024-04-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 92 of the SDHD protein (p.Asp92Tyr). RNA analysis indicates that this missense change induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with paraganglioma and pheochromocytoma (PMID: 19584903, 21348866). It is commonly reported in individuals of Dutch ancestry (PMID: 19584903, 21348866). ClinVar contains an entry for this variant (Variation ID: 6897). 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 affects SDHD function (PMID: 26008905). Studies have shown that this missense change results in skipping of exon 3 and introduces a new termination codon (Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000567104 SCV000664566 pathogenic Hereditary cancer-predisposing syndrome 2022-05-13 criteria provided, single submitter clinical testing The p.D92Y variant (also known as c.274G>T), located in coding exon 3 of the SDHD gene, results from a G to T substitution at nucleotide position 274. The aspartic acid at codon 92 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been detected in multiple individuals with paragangliomas and is noted to be a founder mutation in the Dutch population (Taschner PE et al. Genes Chromosomes Cancer, 2001 Jul;31:274-81; Bayley JP et al. BMC Med. Genet., 2014 Oct;15:111; Hensen EF et al. Eur. J. Hum. Genet., 2010 Jan;18:62-6; Hensen EF et al. Clin. Genet., 2012 Mar;81:284-8; Baysal BE et al. Science, 2000 Feb;287:848-51; van Schothorst EM et al. Am. J. Hum. Genet., 1998 Aug;63:468-73). In addition, this alteration has been shown to strongly segregate with paragangliomas in a large multi-generational family (Hensen EF et al. Eur. J. Hum. Genet., 2010 Jan;18:62-6). This amino acid position is completely conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity RCV001701480 SCV002019158 likely pathogenic not provided 2020-09-09 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV002288471 SCV002581638 pathogenic Paragangliomas 4 2022-01-17 criteria provided, single submitter clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet RCV000020520 SCV005689606 pathogenic Hereditary pheochromocytoma-paraganglioma 2025-01-24 criteria provided, single submitter clinical testing The following ACMG criteria have been used in classification: PM2_SUP; PS4; PP1; PP3; PS3
OMIM RCV000007305 SCV000027502 pathogenic Paragangliomas 1 2012-03-01 no assertion criteria provided literature only
GeneReviews RCV000020520 SCV000040977 not provided Hereditary pheochromocytoma-paraganglioma no assertion provided literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV001701480 SCV001929698 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001701480 SCV001951954 pathogenic not provided no assertion criteria provided clinical testing

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