rs796052053

chr2-84459230-T-Achr2-84459230-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM2 PM5 PP5_Very_Strong BP4

The NM_003849.4(SUCLG1):c.40A>T(p.Met14Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000858 in 1,398,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M14V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: SUCLG1 NM_003849.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.93

Genes affected

SUCLG1 (HGNC:11449): (succinate-CoA ligase GDP/ADP-forming subunit alpha) This gene encodes the alpha subunit of the heterodimeric enzyme succinate coenzyme A ligase. This enzyme is targeted to the mitochondria and catalyzes the conversion of succinyl CoA and ADP or GDP to succinate and ATP or GTP. Mutations in this gene are the cause of the metabolic disorder fatal infantile lactic acidosis and mitochondrial DNA depletion. [provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-84459229-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 632366.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 2-84459230-T-A is Pathogenic according to our data. Variant chr2-84459230-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 561158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.35133097).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUCLG1	NM_003849.4	c.40A>T	p.Met14Leu	missense_variant	1/9	ENST00000393868.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUCLG1	ENST00000393868.7	c.40A>T	p.Met14Leu	missense_variant	1/9	1	NM_003849.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000586 AC: 9 AN: 153666 Hom.: 0 AF XY: 0.0000491 AC XY: 4 AN XY: 81412

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000364

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000858 AC: 12 AN: 1398350 Hom.: 0 Cov.: 31 AF XY: 0.00000725 AC XY: 5 AN XY: 689700

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000308

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial DNA depletion syndrome 9 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This variant has been previously reported as disease-causing and was found once in our laboratory with a missense variant [Q212R - phase not determined, but mother carried M14L and not Q212R] in a 7-year-old female with bilateral hearing loss and congenital chorea. Heterozygotes for this variant are expected to be asymptomatic carriers. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 14 of the SUCLG1 protein (p.Met14Leu). This variant is present in population databases (no rsID available, gnomAD 0.04%). This missense change has been observed in individual(s) with mitochondrial DNA depletion syndrome and/or SUCLG1-related conditions (PMID: 20453710, 27484306; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 561158). 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 SUCLG1 protein function. Studies have shown that this missense change alters SUCLG1 gene expression (PMID: 27484306). This variant disrupts the p.Met14 amino acid residue in SUCLG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21639866, 29217198, 35094435). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Benign	22
Dann	Benign	0.92
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.052
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	0.95	N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.020	N
REVEL	Uncertain	0.54
Sift	Benign	0.59	T
Sift4G	Benign	1.0	T
Polyphen		0.17	B
Vest4		0.43
MutPred		0.34		Loss of catalytic residue at M14 (P = 0.0699);
MVP		0.77
MPC		0.038
ClinPred		0.37	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.55
gMVP		0.76

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

Other links and lift over

dbSNP: rs796052053; hg19: chr2-84686354;