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

gnomAD frequency: 0.00001  dbSNP: rs80338845

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002512869	SCV000287820	pathogenic	Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3	2023-07-21	criteria provided, single submitter	clinical testing	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. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects SDHD function (PMID: 26008905). ClinVar contains an entry for this variant (Variation ID: 6897). 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). This variant is not present in population databases (gnomAD no frequency). 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).
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
OMIM	RCV000007305	SCV000027502	pathogenic	Paragangliomas 1	2012-03-01	no assertion criteria provided	literature only
OMIM	RCV000007306	SCV000027503	pathogenic	Pheochromocytoma	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