5-251446-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_004168.4(SDHA):c.1772C>T(p.Ala591Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,613,862 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. A591T) 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.1772C>T | p.Ala591Val | missense_variant | 13/15 | ENST00000264932.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.1772C>T | p.Ala591Val | missense_variant | 13/15 | 1 | NM_004168.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152204Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251018Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135694
GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461658Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 727138
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74358
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 | Nov 27, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 591 of the SDHA protein (p.Ala591Val). This variant is present in population databases (rs367621815, gnomAD 0.004%). This missense change has been observed in individual(s) with head and neck paraganglioma (PMID: 30050099). ClinVar contains an entry for this variant (Variation ID: 472355). 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 | Oct 09, 2023 | - - |
See cases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Apr 08, 2021 | ACMG classification criteria: PP3 - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 08, 2023 | The p.A591V variant (also known as c.1772C>T), located in coding exon 13 of the SDHA gene, results from a C to T substitution at nucleotide position 1772. The alanine at codon 591 is replaced by valine, an amino acid with similar properties. This variant has been identified in a patient with a head and neck paraganglioma from a cohort of 391 paraganglioma and/or pheochromocytoma patients (Richter S et al. Genet Med, 2019 03;21:705-717).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