rs61754481
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_004168.4(SDHA):āc.613T>Cā(p.Tyr205His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,614,032 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 Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y205C) has been classified as Uncertain significance.
Frequency
Consequence
NM_004168.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.613T>C | p.Tyr205His | missense_variant | 5/15 | ENST00000264932.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.613T>C | p.Tyr205His | missense_variant | 5/15 | 1 | NM_004168.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152162Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251278Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135838
GnomAD4 exome AF: 0.0000287 AC: 42AN: 1461870Hom.: 0 Cov.: 33 AF XY: 0.0000289 AC XY: 21AN XY: 727238
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152162Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74336
ClinVar
Submissions by phenotype
Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | 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. - |
Dilated cardiomyopathy 1GG Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 06, 2023 | - - |
Leigh syndrome;C3150898:Dilated cardiomyopathy 1GG;C3279992:Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 04, 2022 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in an individual with paraganglioma, however this person also harbored a pathogenic SDHB variant (Ben Aim 2019); This variant is associated with the following publications: (PMID: 30877234) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 09, 2024 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at