2-84459230-T-C

Variant names:

• chr2-84459230-T-C
• rs796052053
• NM_003849.4:c.40A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003849.4(SUCLG1):​c.40A>G​(p.Met14Val) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: SUCLG1 NM_003849.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUCLG1	NM_003849.4	c.40A>G	p.Met14Val	missense_variant	Exon 1 of 9	ENST00000393868.7	NP_003840.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUCLG1	ENST00000393868.7	c.40A>G	p.Met14Val	missense_variant	Exon 1 of 9	1	NM_003849.4	ENSP00000377446.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000130 AC: 2 AN: 153666 Hom.: 0 AF XY: 0.0000246 AC XY: 2 AN XY: 81412

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000809

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: 0.0000317

Gnomad4 AMR exome AF: 0.0000560

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: 0.00000834

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mitochondrial DNA depletion syndrome 9 Uncertain:2

Jun 04, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 14 of the SUCLG1 protein (p.Met14Val). This variant is present in population databases (rs796052053, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with SUCLG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 203978). 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) has been performed 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. 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: 20453710, 27484306; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

not provided Pathogenic:1

Jan 15, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37445899, Zhang2020[CaseReport]) -

Inborn genetic diseases Uncertain:1

Jul 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.40A>G (p.M14V) alteration is located in exon 1 (coding exon 1) of the SUCLG1 gene. This alteration results from a A to G substitution at nucleotide position 40, causing the methionine (M) at amino acid position 14 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.0095
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.075	D
MutationAssessor	Uncertain	2.0	M
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.31	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.026	D
Sift4G	Benign	0.10	T
Polyphen		0.32	B
Vest4		0.52
MutPred		0.37		Gain of sheet (P = 0.0028);
MVP		0.92
MPC		0.040
ClinPred		0.80	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.65
gMVP		0.83

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;