rs1042170
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong
The NM_004168.4(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 (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000075 ( 0 hom. )
Consequence
SDHA
NM_004168.4 missense
NM_004168.4 missense
Scores
9
7
3
Clinical Significance
Conservation
PhyloP100: 9.43
Genes affected
SDHA (HGNC:10680): (succinate dehydrogenase complex flavoprotein subunit A) This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.956
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 | ENSP00000264932.6 | ||
ENSG00000286001 | ENST00000651543.1 | n.*504G>A | non_coding_transcript_exon_variant | 12/24 | ENSP00000499215.1 | |||||
ENSG00000286001 | ENST00000651543.1 | n.*504G>A | 3_prime_UTR_variant | 12/24 | ENSP00000499215.1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152226Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000518 AC: 13AN: 250998Hom.: 0 AF XY: 0.0000737 AC XY: 10AN XY: 135684
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GnomAD4 exome AF: 0.0000753 AC: 110AN: 1461630Hom.: 0 Cov.: 32 AF XY: 0.0000743 AC XY: 54AN XY: 727126
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74378
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;D;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;H;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;D;D;D
REVEL
Pathogenic
Sift
Uncertain
.;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
0.99
.;D;.;.
Vest4
MutPred
0.79
.;Gain of glycosylation at A591 (P = 0.0131);.;.;
MVP
MPC
1.2
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at