rs139881415

Variant names:

• chr5-225989-G-A
• rs139881415
• NM_004168.4:c.563G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-225989-G-A
• chr5-225989-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM5 PP3_Moderate PP5

The NM_004168.4(SDHA):​c.563G>A​(p.Arg188Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,022 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R188W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: SDHA NM_004168.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2
• Conservation: PhyloP100: 9.47
• Publications: 4 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: Uncertain_significance. The variant received 5 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-225988-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 472395.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 5-225989-G-A is Pathogenic according to our data. Variant chr5-225989-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 450839.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4	c.563G>A	p.Arg188Gln	missense_variant	Exon 5 of 15	ENST00000264932.11	NP_004159.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11	c.563G>A	p.Arg188Gln	missense_variant	Exon 5 of 15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.563G>A		non_coding_transcript_exon_variant	Exon 5 of 24			ENSP00000499215.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251474 AF XY: 0.00000736

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461850 Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 727220

African (AFR) AF: 0.000149 AC: 5 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152172 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74330

African (AFR) AF: 0.000145 AC: 6 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.0000907

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pheochromocytoma/paraganglioma syndrome 5 Pathogenic:2

Dec 25, 2023

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SDHA c.563G>A (p.Arg188Gln) missense change has a maximum subpopulation frequency of 0.01% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in several individuals with SDHA-related tumors (PMID: 32741965, external communication). In summary, this variant meets criteria to be classified as likely pathogenic. -

Sep 28, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 32741965, Myriad internal data]. This variant is expected to disrupt protein structure [Myriad internal data]. -

not provided Uncertain:2

Mar 09, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15989954, 28724664, 23282968, 32741965) -

May 11, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SDHA c.563G>A (p.Arg188Gln) variant has been reported in the published literature in in an individual with retroperitoneal paraganglioma (PMID: 32741965 (2020)). The frequency of this variant in the general population, 0.00012 (3/24966 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the 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. -

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

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 188 of the SDHA protein (p.Arg188Gln). This variant is present in population databases (rs139881415, gnomAD 0.01%). This missense change has been observed in individuals with gastrointestinal stromal tumor syndrome and/or paragangliomas (PMID: 32741965; external communication, internal data). ClinVar contains an entry for this variant (Variation ID: 450839). 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. This variant disrupts the p.Arg188 amino acid residue in SDHA. Other variant(s) that disrupt this residue have been observed in individuals with SDHA-related conditions (PMID: 23282968; internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 15, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R188Q variant (also known as c.563G>A), located in coding exon 5 of the SDHA gene, results from a G to A substitution at nucleotide position 563. The arginine at codon 188 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been observed in multiple individuals with a paraganglioma or gastrointestinal stromal tumor (Greenberg SE et al. Genet Med, 2020 12;22:2101-2107; Rana HQ et al. Cancers (Basel), 2024 Feb;16:; Ambry internal data). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Neurodegeneration with ataxia and late-onset optic atrophy Pathogenic:1

Dec 26, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SDHA c.563G>A (p.Arg188Gln) 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 damaging effect of the variant on protein function. Another variant located at the same codon (c.562C>T, p.Arg188Trp) has been observed with evidence supporting pathogenicity for SDHA-related conditions, supporting the critical relevance of this residue to SDHA protein function. The variant allele was found at a frequency of 1.2e-05 in 251474 control chromosomes. c.563G>A has been reported in the literature and at our laboratory in individuals affected with gastrointestinal stromal tumor syndrome and/or paragangliomas (Greenberg_2020; external communication, internal data). These data indicate that the variant is likely to be associated with disease. 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: 28724664, 32741965, 34415331, 39133175). ClinVar contains an entry for this variant (Variation ID: 450839). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D;.;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.1	H;.;.
PhyloP100		9.5
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.96
MVP		0.95
MPC		1.5
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.98
gMVP		0.95
Mutation Taster		=44/56	disease causing (ClinVar)

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: rs139881415; hg19: chr5-226104;