rs753904927

Positions:

• chr11-74493327-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001144869.3(LIPT2):​c.377T>G​(p.Leu126Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0003 in 1,476,744 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 0.00019 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: LIPT2 NM_001144869.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 2.46

Genes affected

LIPT2 (HGNC:37216): (lipoyl(octanoyl) transferase 2) This gene encodes a mitochondrial protein that catalyzes the transfer of octanoic acid to lipoate-dependent enzymes such as octanoyl-ACP. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

LIPT2-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88
• PP5: Variant 11-74493327-A-C is Pathogenic according to our data. Variant chr11-74493327-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 438639.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}. Variant chr11-74493327-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIPT2	NM_001144869.3	c.377T>G	p.Leu126Arg	missense_variant	1/2	ENST00000310109.5	NP_001138341.1
LIPT2	NM_001329941.2	c.377T>G	p.Leu126Arg	missense_variant	1/2		NP_001316870.1
LIPT2	NM_001329942.2	c.237+140T>G		intron_variant			NP_001316871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIPT2	ENST00000310109.5	c.377T>G	p.Leu126Arg	missense_variant	1/2	2	NM_001144869.3	ENSP00000309463.4
LIPT2	ENST00000528085.1	c.180+140T>G		intron_variant		3		ENSP00000433005.1
LIPT2-AS1	ENST00000526036.1	n.-39A>C		upstream_gene_variant		1
LIPT2	ENST00000527115.1	c.-14T>G		upstream_gene_variant		2		ENSP00000431210.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152210 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000368

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000168 AC: 14 AN: 83428 Hom.: 0 AF XY: 0.000149 AC XY: 7 AN XY: 47136

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: 0.000418

Gnomad OTH exome AF: 0.000394

GnomAD4 exome AF: 0.000313 AC: 414 AN: 1324416 Hom.: 0 Cov.: 42 AF XY: 0.000316 AC XY: 206 AN XY: 651230

Gnomad4 AFR exome AF: 0.0000739

Gnomad4 AMR exome AF: 0.00

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: 0.000379

Gnomad4 OTH exome AF: 0.000255

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152328 Hom.: 0 Cov.: 34 AF XY: 0.000161 AC XY: 12 AN XY: 74496

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000282 Hom.: 0

Bravo AF: 0.000189

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities Pathogenic:3

Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Apr 16, 2018	This variant is interpreted as a Likely Pathogenic, for Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PS3 => Well-established functional studies show a deleterious effect (PMID:28757203). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (PMID:28757203). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:28757203). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 04, 2018	- -

LIPT2-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 02, 2023

The LIPT2 c.377T>G variant is predicted to result in the amino acid substitution p.Leu126Arg. This variant was reported in a compound heterozygous individual with severe neonatal encephalopathy (Habarou et al 2017. PubMed ID: 28757203). Biochemical and functional studies support pathogenicity for the c.377T>C change (Lebigot E et al 2017. PubMed ID: 28803783). This variant is reported in 0.045% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-74204372-A-C). This variant is interpreted as likely pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 19, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 438639). This missense change has been observed in individuals with neonatal encephalopathy with lactic acidosis and brain anomalies (PMID: 28757203). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs753904927, gnomAD 0.04%). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 126 of the LIPT2 protein (p.Leu126Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.031	D
Polyphen		0.98	D
Vest4		0.60
MVP		0.61
ClinPred		0.45	T
GERP RS		4.7
Varity_R		0.74
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs753904927; hg19: chr11-74204372;