NM_004168.4:c.778G>C

Variant names:

• chr5-230883-G-C
• rs940845256
• NM_004168.4:c.778G>C

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS1_Very_Strong PM2 PP3_Strong PP5_Very_Strong

The NM_004168.4(SDHA):​c.778G>C​(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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G260E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SDHA NM_004168.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.13
• Publications: 0 publications found

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]

SDHA Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• pheochromocytoma/paraganglioma syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• mitochondrial complex II deficiency, nuclear type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• neurodegeneration with ataxia and late-onset optic atrophy

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics, ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• gastrointestinal stromal tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex II deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1GG

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000286001 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS1: Transcript NM_004168.4 (SDHA) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 412357
• 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
SDHA	NM_004168.4	c.778G>C	p.Gly260Arg	missense_variant	Exon 7 of 15	ENST00000264932.11	NP_004159.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11	c.778G>C	p.Gly260Arg	missense_variant	Exon 7 of 15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.778G>C		non_coding_transcript_exon_variant	Exon 7 of 24			ENSP00000499215.1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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

Jan 09, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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

Feb 14, 2022

DASA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same 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;.;.
PhyloP100		9.1
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
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs940845256; hg19: chr5-230998;