rs1042170
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_Strong
The ENST00000264932.11(SDHA):c.1771G>A(p.Ala591Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,613,856 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. A591V) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000264932.11 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.1771G>A | p.Ala591Thr | missense_variant | 13/15 | ENST00000264932.11 | NP_004159.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.1771G>A | p.Ala591Thr | missense_variant | 13/15 | 1 | NM_004168.4 | ENSP00000264932 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152226Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000518 AC: 13AN: 250998Hom.: 0 AF XY: 0.0000737 AC XY: 10AN XY: 135684
GnomAD4 exome AF: 0.0000753 AC: 110AN: 1461630Hom.: 0 Cov.: 32 AF XY: 0.0000743 AC XY: 54AN XY: 727126
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74378
ClinVar
Submissions by phenotype
Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 591 of the SDHA protein (p.Ala591Thr). This variant is present in population databases (rs1042170, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of SDHA-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 412370). 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 | Sep 26, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 28, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with multiple paraganglioma who also carried a splice variant in the SDHD gene (PMID: 33715142); This variant is associated with the following publications: (PMID: 33715142) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 27, 2023 | The p.A591T variant (also known as c.1771G>A), located in coding exon 13 of the SDHA gene, results from a G to A substitution at nucleotide position 1771. The alanine at codon 591 is replaced by threonine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with a paraganglioma and/or pheochromocytoma however they were also identified to carry an SDHD alteration (Meijs AC et al. J Endocrinol Invest, 2021 Oct;44:2253-2259). 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