rs370690436

Positions:

chr5-236519-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5

The NM_004168.4(SDHA):c.1352G>A(p.Arg451His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,928 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SDHA
NM_004168.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

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]

SDHA links:

ENSG00000286001 (HGNC:):

ENSG00000286001 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity SDHA_HUMAN

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

PP5

Variant 5-236519-G-A is Pathogenic according to our data. Variant chr5-236519-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 581412.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}. Variant chr5-236519-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHA	NM_004168.4 linkuse as main transcript	c.1352G>A	p.Arg451His	missense_variant	10/15	ENST00000264932.11	NP_004159.2	P31040-1A0A024QZ30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SDHA	ENST00000264932.11 linkuse as main transcript	c.1352G>A	p.Arg451His	missense_variant	10/15	1	NM_004168.4	ENSP00000264932.6	P31040-1
ENSG00000286001	ENST00000651543.1 linkuse as main transcript	n.*85G>A		non_coding_transcript_exon_variant	9/24			ENSP00000499215.1	A0A494C1T6
ENSG00000286001	ENST00000651543.1 linkuse as main transcript	n.*85G>A		3_prime_UTR_variant	9/24			ENSP00000499215.1	A0A494C1T6

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152258

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251174

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135744

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461670

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74390

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	May 03, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 12, 2024	The p.R451H variant (also known as c.1352G>A), located in coding exon 10 of the SDHA gene, results from a G to A substitution at nucleotide position 1352. The arginine at codon 451 is replaced by histidine, an amino acid with highly similar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with SDHA-related disease (Toledo RA et al. Clin Cancer Res, 2016 05;22:2301-10; Bannon AE et al. Clin Cancer Res, 2017 Nov;23:6733-6743; van der Tuin K et al. J Clin Endocrinol Metab, 2018 02;103:438-445; Ambry internal data). In one study, the R451H variant was unable to grow on glycerol as carbon source, had decreased oxygen consumption and decreased Sdh2 protein. Computational modeling showed this variant disrupts flavin binding, succinate binding, and proton shuttle necessary for catalytic activity (Bannon AE et al. Clin Cancer Res, 2017 Nov;23:6733-6743). 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. -

Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 25, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 451 of the SDHA protein (p.Arg451His). This variant is present in population databases (rs370690436, gnomAD 0.0009%). This missense change has been observed in individuals with paraganglioma and pheochromocytoma (PMID: 26700204, 29177515; Invitae). ClinVar contains an entry for this variant (Variation ID: 581412). 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. Experimental studies have shown that this missense change affects SDHA function (PMID: 28724664). For these reasons, this variant has been classified as Pathogenic. -

Dilated cardiomyopathy 1GG

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

KTest Genetics, KTest

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

D;D;.;.

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

5.0

.;H;.;.

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-4.5

.;D;D;D

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

.;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.99

MVP

0.85

MPC

1.6

ClinPred

0.99

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.90

gMVP

0.97

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.

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