ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.275A>T (p.Asp92Val)

dbSNP: rs786205436
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479419 SCV000569592 likely pathogenic not provided 2016-04-14 criteria provided, single submitter clinical testing This variant is denoted SDHD c.275A>T at the cDNA level, p.Asp92Val (D92V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAC>GTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign; however, another variant at the same residue, SDHD Asp92Tyr, is a well described Dutch pathogenic founder variant (van Schothorst 1998, Hensen 2010). SDHD Asp92Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Valine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. SDHD Asp92Val occurs at a position that is conserved across species and is located in the transmembrane helical domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider SDHD Asp92Val to be a likely pathogenic variant.
Invitae RCV002525847 SCV000640156 likely pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3 2022-05-20 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) performed at Invitae indicates that this missense variant is expected to disrupt SDHD protein function. ClinVar contains an entry for this variant (Variation ID: 420665). This missense change has been observed in individual(s) with paraganglioma (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 92 of the SDHD protein (p.Asp92Val). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asp92 amino acid residue in SDHD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19584903, 21348866). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
Ambry Genetics RCV000569878 SCV000664532 likely pathogenic Hereditary cancer-predisposing syndrome 2017-10-17 criteria provided, single submitter clinical testing The p.D92V likely pathogenic variant (also known as c.275A>T), located in coding exon 3 of the SDHD gene, results from an A to T substitution at nucleotide position 275. The aspartic acid at codon 92 is replaced by valine, an amino acid with highly dissimilar properties. Though this exact alteration has not been reported in the literature, a mutation at the same codon, p.D92Y, is recognized as a Dutch founder mutation and has been reported in multiple individuals with paraganglioma-pheochromocytoma syndrome (PGL/PCC) (Hensen EF et al. Clin. Genet. 2012 Mar;81(3):284-8). Another mutation at the same codon, p.D92G, has been reported in a homozygous individual who passed away in infancy from severe mitochondrial complex II deficiency (Alston CL et al. Hum. Genet. 2015 Aug;134(8):869-79). Structural analysis of the p.D92V alteration suggests that this variant disrupts the folding of SDHD to a higher degree than the known pathogenic variants p.D92Y and p.D92G at the same position, leading either to reduction or loss of protein function (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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