ClinVar Miner

Submissions for variant NM_004168.4(SDHA):c.613T>C (p.Tyr205His)

gnomAD frequency: 0.00003  dbSNP: rs61754481
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000471598 SCV000553840 uncertain significance Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 205 of the SDHA protein (p.Tyr205His). This variant is present in population databases (rs61754481, gnomAD 0.01%). This missense change has been observed in individual(s) with a paraganglioma (PMID: 30877234). ClinVar contains an entry for this variant (Variation ID: 412329). 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 SDHA protein function. 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 RCV000575607 SCV000674920 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-09 criteria provided, single submitter clinical testing The p.Y205H variant (also known as c.613T>C), located in coding exon 5 of the SDHA gene, results from a T to C substitution at nucleotide position 613. The tyrosine at codon 205 is replaced by histidine, an amino acid with similar properties. This variant was identified in an individual with benign abdominal paraganglioma but co-occurred with a pathogenic SDHB alteration (p.Arg90Ter) (Ben Aim L et al. J Med Genet, 2019 Aug;56:513-520). This alteration was classified as a variant of unknown significance by authors who reported it in a French dilated cardiomyopathy (DCM) cohort (Perret C et al. Clin Genet, 2024 Feb;105:185-189). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV000764602 SCV000895699 uncertain significance Leigh syndrome; Mitochondrial complex II deficiency, nuclear type 1; Dilated cardiomyopathy 1GG; Paragangliomas 5 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV001848822 SCV002104466 uncertain significance not provided 2023-11-14 criteria provided, single submitter clinical testing Observed in an individual with paraganglioma, however this person also harbored a pathogenic SDHB variant (PMID: 30877234); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30877234)
Baylor Genetics RCV003476119 SCV004200564 uncertain significance Dilated cardiomyopathy 1GG 2023-12-06 criteria provided, single submitter clinical testing

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