5-251425-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_004168.4(SDHA):c.1751C>T(p.Ala584Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000973 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A584A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

SDHA
NM_004168.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5

Conservation

PhyloP100: 5.78

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]

SDHA links:

ENSG00000286001 (HGNC:):

ENSG00000286001 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4 link	c.1751C>T	p.Ala584Val	missense_variant	Exon 13 of 15	ENST00000264932.11	NP_004159.2	P31040-1A0A024QZ30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SDHA	ENST00000264932.11 link	c.1751C>T	p.Ala584Val	missense_variant	Exon 13 of 15	1	NM_004168.4	ENSP00000264932.6	P31040-1
ENSG00000286001	ENST00000651543.1 link	n.*484C>T		non_coding_transcript_exon_variant	Exon 12 of 24			ENSP00000499215.1	A0A494C1T6
ENSG00000286001	ENST00000651543.1 link	n.*484C>T		3_prime_UTR_variant	Exon 12 of 24			ENSP00000499215.1	A0A494C1T6

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000916

AC:

AN:

251008

Hom.:

AF XY:

0.0000884

AC XY:

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000203

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000985

AC:

144

AN:

1461652

Hom.:

Cov.:

AF XY:

0.0000894

AC XY:

AN XY:

727136

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:

0.000123

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Jan 15, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; While this variant is considered pathogenic for autosomal recessive Complex II deficiency, its association with autosomal dominant Hereditary Paraganglioma/Pheochromocytoma syndrome is unclear; Observed in a patient with paraganglioma; this patient also had a variant in the SDHB gene with loss of SDHB expression in the tumor (PMID: 35546442); This variant is associated with the following publications: (PMID: 30680959, 28546994, 35546442) -

not specified

Uncertain:1

Feb 20, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SDHA c.1751C>T (p.Ala584Val) results in a non-conservative amino acid change located in the C-terminal domain (IPR015939) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Additionally, several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.2e-05 in 251008 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1751C>T has been reported in the literature in at least one individual affected with paraganglioma (e.g., Ding_2022), however, the variant was found to co-occur with another pathogenic variant (SDHB c.3G>A, p.M1I), providing supporting evidence for a benign role. This report therefore does not provide unequivocal conclusions about association of the variant with SDHA-related disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 35546442). ClinVar contains an entry for this variant (Variation ID: 239657). 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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 584 of the SDHA protein (p.Ala584Val). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 15 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs201068049, gnomAD 0.02%). 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: 239657). 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) indicates that this missense variant is not expected to disrupt SDHA protein function with a negative predictive value of 95%. Studies have shown that this missense change results in the activation of a cryptic splice site in exon 13 (internal data). 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

Mar 04, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Aug 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1751C>T variant (also known as p.A584V), located in coding exon 13 of the SDHA gene, results from a C to T substitution at nucleotide position 1751. The alanine at codon 584 is replaced by valine, an amino acid with similar properties. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). In addition, this variant has been detected in multiple heterozygous and homozygous individuals with no reported features of SDHA-associated disease (Ambry internal data). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

SDHA-related disorder

Uncertain:1

Jul 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SDHA c.1751C>T variant is predicted to result in the amino acid substitution p.Ala584Val. This variant is predicted to activate a cryptic splice donor site in exon 13 based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751), however mRNA studies have not been reported in the literature. To our knowledge, this variant has not been reported in individuals with SDHA-associated disorders in the literature. An alternate substitution of this amino acid (p.Ala584Thr) has been reported with uncertain significance in a cohort of individuals with breast cancer (McDonald et al. 2022. PubMed ID: 36315513). This variant is reported in 0.021% of alleles in individuals of European (Non-Finnish) descent in gnomAD, and has conflicting interpretations of pathogenicity in ClinVar ranging from uncertain to likely pathogenic (http://www.ncbi.nlm.nih.gov/clinvar/variation/239657). 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

Benign

0.16

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

T;D;.;D

Eigen

Benign

0.13

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.69

D;D;D;D

MetaSVM

Uncertain

0.34

MutationAssessor

Pathogenic

3.0

.;M;.;.

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.5

.;N;D;D

REVEL

Pathogenic

0.65

Sift

Benign

0.097

.;T;T;D

Sift4G

Benign

0.28

T;T;T;T

Polyphen

0.065

.;B;.;.

Vest4

0.67

MVP

0.84

MPC

0.54

ClinPred

0.20

GERP RS

3.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.56

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.98

Position offset: -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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over