chr13-47968646-C-T

Variant names:

• chr13-47968646-C-T
• rs397515462
• NM_003850.3:c.751G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_003850.3(SUCLA2):​c.751G>A​(p.Asp251Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,474 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SUCLA2 NM_003850.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.27
• Publications: 7 publications found

Genes affected

SUCLA2 (HGNC:11448): (succinate-CoA ligase ADP-forming subunit beta) Succinyl-CoA synthetase (SCS) is a mitochondrial matrix enzyme that acts as a heterodimer, being composed of an invariant alpha subunit and a substrate-specific beta subunit. The protein encoded by this gene is an ATP-specific SCS beta subunit that dimerizes with the SCS alpha subunit to form SCS-A, an essential component of the tricarboxylic acid cycle. SCS-A hydrolyzes ATP to convert succinate to succinyl-CoA. Defects in this gene are a cause of myopathic mitochondrial DNA depletion syndrome. A pseudogene of this gene has been found on chromosome 6. [provided by RefSeq, Jul 2008]

SUCLA2 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria

  Inheritance: Mitochondrial, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897
• PP5: Variant 13-47968646-C-T is Pathogenic according to our data. Variant chr13-47968646-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 66034.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUCLA2	NM_003850.3	c.751G>A	p.Asp251Asn	missense_variant	Exon 6 of 11	ENST00000646932.1	NP_003841.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUCLA2	ENST00000646932.1	c.751G>A	p.Asp251Asn	missense_variant	Exon 6 of 11		NM_003850.3	ENSP00000494360.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459474 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726054

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 86160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4164

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111752

Other (OTH) AF: 0.00 AC: 0 AN: 60192

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria Pathogenic:2 Uncertain:1

Aug 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 03, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individual(s) with clinical features of SUCLA2-related conditions (PMID: 23759946). It has also been observed to segregate with disease in related individuals. 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. 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) performed at Invitae indicates that this missense variant is expected to disrupt SUCLA2 protein function. ClinVar contains an entry for this variant (Variation ID: 66034). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 251 of the SUCLA2 protein (p.Asp251Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D;D;.;.;.;D;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D;.;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.0	M;M;.;.;.;.;.
PhyloP100		7.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.7	.;D;.;.;.;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	.;D;.;.;.;D;D
Sift4G	Uncertain	0.048	.;D;.;.;.;D;.
Polyphen		1.0	D;D;.;.;.;.;.
Vest4		0.98
MutPred		0.78		Gain of catalytic residue at I255 (P = 0.0021);Gain of catalytic residue at I255 (P = 0.0021);Gain of catalytic residue at I255 (P = 0.0021);.;.;.;.;
MVP		0.92
MPC		0.85
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.94
gMVP		0.83
Mutation Taster		=3/97	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: rs397515462; hg19: chr13-48542781;