chr5-230883-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1PM2PP3_StrongPP5_Very_Strong

The NM_004168.4(SDHA):ā€‹c.778G>Cā€‹(p.Gly260Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā˜…ā˜…). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in Lovd.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

SDHA
NM_004168.4 missense

Scores

15
3
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.13
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 Pathogenic. Variant got 18 ACMG points.

PS1
Transcript NM_004168.4 (SDHA) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
Variant 5-230883-G-C is Pathogenic according to our data. Variant chr5-230883-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1066704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SDHANM_004168.4 linkc.778G>C p.Gly260Arg missense_variant Exon 7 of 15 ENST00000264932.11 NP_004159.2 P31040-1A0A024QZ30

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SDHAENST00000264932.11 linkc.778G>C p.Gly260Arg missense_variant Exon 7 of 15 1 NM_004168.4 ENSP00000264932.6 P31040-1
ENSG00000286001ENST00000651543.1 linkn.778G>C non_coding_transcript_exon_variant Exon 7 of 24 ENSP00000499215.1 A0A494C1T6

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461852
Hom.:
0
Cov.:
56
AF XY:
0.00
AC XY:
0
AN XY:
727228
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 15, 2025This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 260 of the SDHA protein (p.Gly260Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paraganglioma or pheochromocytoma (PMID: 25394176, 28384794, 33397043; external communication, internal data). ClinVar contains an entry for this variant (Variation ID: 1066704). Invitae Evidence 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 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. Experimental studies have shown that this missense change affects SDHA function (PMID: 28724664). For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJan 09, 2023The p.G260R pathogenic mutation (also known as c.778G>C), located in coding exon 7 of the SDHA gene, results from a G to C substitution at nucleotide position 778. The glycine at codon 260 is replaced by arginine, an amino acid with dissimilar properties. Another alteration at the same codon, p.G260R (c.778G>A), has been detected in individuals with pheochromocytoma, paraganglioma, or SDH-deficient renal cell carcinoma (Evenepoel L et al. Genet. Med., 2015 Aug;17:610-20; Bausch B et al. JAMA Oncol, 2017 Sep;3:1204-1212; Ambry internal data). Furthermore, a functional study demonstrated that yeast equivalent of this variant (G251R) impairs function of succinate dehydrogenase complex (Bannon AE et al. Clin. Cancer Res., 2017 Nov;23:6733-6743). Based on internal structural analysis, p.G260R is anticipated to result in a significant decrease in structural stability (Inaoka DK et al. Int J Mol Sci, 2015 Jul;16:15287-308). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Neurodegeneration with ataxia and late-onset optic atrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingDASAFeb 14, 2022Same amino acid variant as a previously established pathogenic variant regardless of nucleotide variant (ClinVar ID: 412357 - c.778G>A;p.(Gly260Arg); PMID: 25394176, 28384794) - PS1. The c.778G>C;p.(Gly260Arg) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 1066704) - PS4_supporting. This variant is not present in population databases (gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.37
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.66
D;.;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
0.89
D
MutationAssessor
Pathogenic
5.1
H;.;.
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-6.9
D;D;D
REVEL
Pathogenic
0.84
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;.
Vest4
0.98
MutPred
0.92
Gain of methylation at G260 (P = 0.0163);Gain of methylation at G260 (P = 0.0163);.;
MVP
0.94
MPC
1.5
ClinPred
1.0
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.97
gMVP
0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-230998; API