chr5-236467-G-A

Position:

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

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 9.58
Variant links:
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
SDHANM_004168.4 linkuse as main transcriptc.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
SDHAENST00000264932.11 linkuse as main transcriptc.1300G>A p.Gly434Ser missense_variant 10/151 NM_004168.4 ENSP00000264932 P1P31040-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152218
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251068
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135708
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000178
AC:
26
AN:
1461604
Hom.:
0
Cov.:
31
AF XY:
0.00000963
AC XY:
7
AN XY:
727120
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152336
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000480
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000165
AC:
2

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 submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJan 20, 2023The 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 submitterclinical testingGeneDxAug 24, 2023Not 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 10, 2024Variant 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 28, 2024This 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 submitterclinical testingAmbry GeneticsSep 16, 2023The 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 providedclinical testingPreventionGenetics, part of Exact SciencesNov 27, 2023The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.67
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.66
D;D;.;.
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.88
D;D;D;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Pathogenic
0.99
D;D;D;D
MetaSVM
Pathogenic
0.92
D
MutationAssessor
Pathogenic
4.4
.;H;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-5.4
.;D;D;D
REVEL
Pathogenic
0.89
Sift
Uncertain
0.0010
.;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D
Polyphen
1.0, 1.0
.;D;D;.
Vest4
0.96
MutPred
0.94
.;Loss of catalytic residue at L435 (P = 0.1168);Loss of catalytic residue at L435 (P = 0.1168);.;
MVP
0.93
MPC
1.2
ClinPred
0.99
D
GERP RS
5.0
Varity_R
0.82
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs529198317; hg19: chr5-236582; COSMIC: COSV53771023; COSMIC: COSV53771023; API