rs754893758
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_Strong
The NM_004168.4(SDHA):c.1324G>A(p.Ala442Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,736 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A442V) has been classified as Uncertain significance.
Frequency
Consequence
NM_004168.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.1324G>A | p.Ala442Thr | missense_variant | 10/15 | ENST00000264932.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.1324G>A | p.Ala442Thr | missense_variant | 10/15 | 1 | NM_004168.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152228Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251152Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135744
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461508Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727084
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74366
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1GG;C3279992:Paragangliomas 5;C5543254:Neurodegeneration with ataxia and late-onset optic atrophy;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 24, 2021 | - - |
Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 24, 2023 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 539668). This variant has not been reported in the literature in individuals affected with SDHA-related conditions. This variant is present in population databases (rs754893758, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 442 of the SDHA protein (p.Ala442Thr). - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 05, 2023 | The p.A442T variant (also known as c.1324G>A), located in coding exon 10 of the SDHA gene, results from a G to A substitution at nucleotide position 1324. The alanine at codon 442 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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