chr5-236467-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong
The NM_004168.4(SDHA):c.1300G>A(p.Gly434Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,613,940 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 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
SDHA
NM_004168.4 missense
NM_004168.4 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 9.58
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, 0.989
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.1300G>A | p.Gly434Ser | missense_variant | 10/15 | ENST00000264932.11 | NP_004159.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.1300G>A | p.Gly434Ser | missense_variant | 10/15 | 1 | NM_004168.4 | ENSP00000264932 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152218Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251068Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135708
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GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461604Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727120
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152336Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74488
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 20, 2023 | The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000025 (7/282462 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 24, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 10, 2024 | Variant summary: SDHA c.1300G>A (p.Gly434Ser) results in a non-conservative amino acid change located in the FAD-dependent oxidoreductase 2, FAD binding domain (IPR003953) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251068 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1300G>A in individuals affected with Neurodegeneration With Ataxia And Late-Onset Optic Atrophy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 472319). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
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 | Jan 28, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 434 of the SDHA protein (p.Gly434Ser). This variant is present in population databases (rs529198317, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with SDHA-related conditions. ClinVar contains an entry for this variant (Variation ID: 472319). 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 16, 2023 | The p.G434S variant (also known as c.1300G>A), located in coding exon 10 of the SDHA gene, results from a G to A substitution at nucleotide position 1300. The glycine at codon 434 is replaced by serine, an amino acid with similar properties. 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. - |
SDHA-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 27, 2023 | The SDHA c.1300G>A variant is predicted to result in the amino acid substitution p.Gly434Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;H;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;D;D;D
REVEL
Pathogenic
Sift
Uncertain
.;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
1.0, 1.0
.;D;D;.
Vest4
MutPred
0.94
.;Loss of catalytic residue at L435 (P = 0.1168);Loss of catalytic residue at L435 (P = 0.1168);.;
MVP
MPC
1.2
ClinPred
D
GERP RS
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