5-251100-C-T

Position:

chr5-251100-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3_StrongPP5

The NM_004168.4(SDHA):c.1660C>T(p.Arg554Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,611,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 0.000017 ( 0 hom. )

Consequence

SDHA
NM_004168.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:1

Conservation

PhyloP100: 2.27

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 5 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 5-251100-C-T is Pathogenic according to our data. Variant chr5-251100-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8742.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=8}. Variant chr5-251100-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHA	NM_004168.4 linkuse as main transcript	c.1660C>T	p.Arg554Trp	missense_variant	12/15	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.1660C>T	p.Arg554Trp	missense_variant	12/15	1	NM_004168.4	ENSP00000264932.6	P31040-1
ENSG00000286001	ENST00000651543.1 linkuse as main transcript	n.*393C>T		non_coding_transcript_exon_variant	11/24			ENSP00000499215.1	A0A494C1T6
ENSG00000286001	ENST00000651543.1 linkuse as main transcript	n.*393C>T		3_prime_UTR_variant	11/24			ENSP00000499215.1	A0A494C1T6

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251134

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135718

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1459274

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

725984

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mitochondrial complex II deficiency, nuclear type 1

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 16, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with SDHA-related disorders. (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - Variants in this gene are known to have reduced penetrance for paragangliomas 5 (PMID: 29978154). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 10 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 74 heterozygotes, 1 homozygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Succ_DH_flav_C domain (DECIPHER). (I) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence of pathogenicity. The p.(Arg554Gln) variant has been classified as a VUS, likely benign and benign in clinical cases in ClinVar. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been identified as homozygous in two sisters diagnosed with Leigh syndrome (PMID: 7550341, PMID: 33162331). The variant has also been classified as likely pathogenic and a VUS in clinical cases in ClinVar. (SP) 0906 - Segregation evidence for this variant is inconclusive. The variant has been shown to segregate in one family with two affected siblings (PMID: 7550341). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Complex II deficiency was shown in muscle, skin fibroblasts and lymphocytes from patient samples, as well as a deleterious effect on the catalytic activity of the SDH protein in yeast (PMID: 7550341, PMID: 20489732). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1995	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 02, 2019	DNA sequence analysis of the SDHA gene demonstrated a sequence change, c.1660C>T, in exon 12 that results in an amino acid change, p.Arg554Trp. The p.Arg554Trp change affects a highly conserved amino acid residue located in a domain of the SDHA protein that is known to be functional. This sequence change has been described in the gnomAD database with a population frequency of 0.014% in the Latino subpopulation (dbSNP rs9809219). The p.Arg554Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2022	Functional analysis found R554W is associated with significantly reduced SDH activity (Bourgeron et al., 1995; Xiao et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 7550341, 11423010, 20489732, 22677546, 16195397, 1492653, 16798039, 21858060) -

Leigh syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 03, 2024

- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 554 of the SDHA protein (p.Arg554Trp). This variant is present in population databases (rs9809219, gnomAD 0.01%). This missense change has been observed in individual(s) with mitochondrial complex II deficiency presenting as Leigh syndrome (PMID: 7550341). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8742). 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: 7550341, 16195397, 20489732, 22677546). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Dilated cardiomyopathy 1GG

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 17, 2024

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2024

The p.R554W variant (also known as c.1660C>T), located in coding exon 12 of the SDHA gene, results from a C to T substitution at nucleotide position 1660. The arginine at codon 554 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was detected in an individual with paraganglioma diagnosed before age 50 (Ambry internal data). This alteration has also been detected in a homozygous state in two siblings with Leigh syndrome and was found to have a deleterious effect on the catalytic activity of the SDH protein in yeast (Bourgeron T et al. Nat. Genet., 1995 Oct;11:144-9). Additional functional studies have shown that this alteration impairs SDHA protein activity (Mbaya E et al. Cell Death Differ., 2010 Dec;17:1855-66; Xiao M et al. Genes Dev., 2012 Jun;26:1326-38). This variant has been reported in conjunction with SDHA c.1549A>G in an 11 year old with dilated cardiomyopathy; however, authors did not comment on the phase of these alterations and no additional clinical information was provided (Gran F et al. Eur J Pediatr, 2022 Jan;181:287-294). 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. -

Diffuse midline glioma, H3 K27-altered

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital

Feb 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;D;.

Eigen

Uncertain

0.21

Eigen_PC

Benign

-0.039

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Uncertain

0.53

MutationAssessor

Pathogenic

3.2

.;M;.

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-6.5

.;D;D

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.95

MutPred

0.92

.;Loss of MoRF binding (P = 0.0729);.;

MVP

0.83

MPC

1.4

ClinPred

0.98

GERP RS

-0.72

Varity_R

0.85

gMVP

0.85

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