rs762108779
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_004168.4(SDHA):c.629G>A(p.Arg210Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,613,338 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
SDHA
NM_004168.4 missense
NM_004168.4 missense
Scores
4
6
9
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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.629G>A | p.Arg210Gln | missense_variant | 6/15 | ENST00000264932.11 | NP_004159.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.629G>A | p.Arg210Gln | missense_variant | 6/15 | 1 | NM_004168.4 | ENSP00000264932.6 | ||
ENSG00000286001 | ENST00000651543.1 | n.629G>A | non_coding_transcript_exon_variant | 6/24 | ENSP00000499215.1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151762Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000319 AC: 8AN: 251134Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135738
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GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461576Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23AN XY: 727096
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 151762Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2AN XY: 74074
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 05, 2023 | Variant summary: SDHA c.629G>A (p.Arg210Gln) results in a conservative amino acid change located in the FAD-dependent oxidoreductase 2, FAD binding domain (IPR003953) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251134 control chromosomes (i.e., 8 heterozygotes; gnomAD v2.1.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.629G>A has been reported in the literature in individual(s) with pheochromocytoma and paraganglioma (e.g., Welander_2014, Bausch_2017), however without strong evidence for causality. These reports therefore do not provide unequivocal conclusions about association of the variant with Neurodegeneration With Ataxia And Late-Onset Optic Atrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28384794, 24694336). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. 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 | Nov 27, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 210 of the SDHA protein (p.Arg210Gln). This variant is present in population databases (rs762108779, gnomAD 0.005%). This missense change has been observed in individual(s) with pheochromocytoma and paraganglioma (PMID: 24694336, 28384794). ClinVar contains an entry for this variant (Variation ID: 567705). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SDHA protein function with a negative predictive value of 95%. 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 | Jan 03, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 02, 2024 | The p.R210Q variant (also known as c.629G>A), located in coding exon 6 of the SDHA gene, results from a G to A substitution at nucleotide position 629. The arginine at codon 210 is replaced by glutamine, an amino acid with highly similar properties. This alteration was reported in an individual with an apparently sporadic pheochromocytoma (Welander J et al. J. Clin. Endocrinol. Metab., 2014 Jul;99:E1352-60). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;.
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N
REVEL
Pathogenic
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
P;B;.
Vest4
MutPred
Loss of phosphorylation at T213 (P = 0.0913);Loss of phosphorylation at T213 (P = 0.0913);.;
MVP
MPC
ClinPred
T
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