chr11-112088971-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_003002.4(SDHD):c.274G>T(p.Asp92Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D92G) has been classified as Pathogenic.
Frequency
Consequence
NM_003002.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHD | NM_003002.4 | c.274G>T | p.Asp92Tyr | missense_variant | 3/4 | ENST00000375549.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHD | ENST00000375549.8 | c.274G>T | p.Asp92Tyr | missense_variant | 3/4 | 1 | NM_003002.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74334
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 09, 2020 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 21, 2023 | 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). - |
Paragangliomas 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2012 | - - |
Paragangliomas 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jan 17, 2022 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 13, 2022 | 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. - |
Hereditary pheochromocytoma-paraganglioma Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at