chr2-99162249-C-G

Variant names:

• chr2-99162249-C-G
• rs137973334
• NM_145199.3:c.292C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PP3_Strong PP5

The NM_145199.3(LIPT1):​c.292C>G​(p.Arg98Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,613,220 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). ClinVar reports functional evidence for this variant: "SCV001782387: Published functional studies in patient fibroblasts demonstrate that transfection of wildtype LIPT1 enzyme rescued PDHC complex activity, whereas transfection of R98G LIPT1 enzyme did not (Tort et al., 2014)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R98Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: LIPT1 NM_145199.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 1.14
• Publications: 6 publications found

Genes affected

LIPT1 (HGNC:29569): (lipoyltransferase 1) The process of transferring lipoic acid to proteins is a two-step process. The first step is the activation of lipoic acid by lipoate-activating enzyme to form lipoyl-AMP. For the second step, the protein encoded by this gene transfers the lipoyl moiety to apoproteins. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 13. Read-through transcription also exists between this gene and the neighboring downstream mitochondrial ribosomal protein L30 (MRPL30) gene. [provided by RefSeq, Mar 2011]

ENSG00000273155 (HGNC:):

MITD1 (HGNC:25207): (microtubule interacting and trafficking domain containing 1) Abscission, the separation of daughter cells at the end of cytokinesis, is effected by endosomal sorting complexes required for transport III (ESCRT-III). The protein encoded by this gene functions as a homodimer, with the N-termini binding to a subset of ESCRT-III subunits and the C-termini binding to membranes. The encoded protein regulates ESCRT-III activity and is required for proper cytokinesis. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001782387: Published functional studies in patient fibroblasts demonstrate that transfection of wildtype LIPT1 enzyme rescued PDHC complex activity, whereas transfection of R98G LIPT1 enzyme did not (Tort et al., 2014); PMID:24256811; SCV003802784: transfection of patient fibroblasts with the c.292C>G variant did not restore lipoylation of mitochondrial proteins, PDHC activity, or increase the oxidation rate of pyruvate or leucine, suggesting a loss of function consequence. PMID:24256811
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 2-99162249-C-G is Pathogenic according to our data. Variant chr2-99162249-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 189836.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145199.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPT1	NM_145199.3	MANE Select	c.292C>G	p.Arg98Gly	missense	Exon 2 of 2	NP_660200.1	Q9Y234
	LIPT1	NM_001204830.2		c.292C>G	p.Arg98Gly	missense	Exon 3 of 3	NP_001191759.1	Q9Y234
	LIPT1	NM_015929.4		c.292C>G	p.Arg98Gly	missense	Exon 3 of 3	NP_057013.1	Q9Y234

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPT1	ENST00000651691.1	MANE Select	c.292C>G	p.Arg98Gly	missense	Exon 2 of 2	ENSP00000498546.1	Q9Y234
	LIPT1	ENST00000393473.6	TSL:1	c.292C>G	p.Arg98Gly	missense	Exon 3 of 3	ENSP00000377115.2	Q9Y234
	ENSG00000273155	ENST00000410042.1	TSL:2	c.-28+5823C>G		intron	N/A	ENSP00000387111.1

Frequencies

GnomAD3 genomes AF: 0.000119 AC: 18 AN: 151876 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000484

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: 0.000221

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000116 AC: 29 AN: 249996 AF XY: 0.000111

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000183 AC: 267 AN: 1461228 Hom.: 0 Cov.: 32 AF XY: 0.000187 AC XY: 136 AN XY: 726926

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52814

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000229 AC: 255 AN: 1111966

Other (OTH) AF: 0.0000497 AC: 3 AN: 60390

GnomAD4 genome AF: 0.000118 AC: 18 AN: 151992 Hom.: 0 Cov.: 31 AF XY: 0.0000808 AC XY: 6 AN XY: 74298

African (AFR) AF: 0.0000483 AC: 2 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67974

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.000207 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000382

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	not provided (3)
2	-	-	Lipoyl transferase 1 deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		1.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MVP		0.86
ClinPred		0.96	D
GERP RS		4.0
Varity_R		0.88
gMVP		0.94
Mutation Taster		=2/98	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: rs137973334; hg19: chr2-99778712; COSMIC: COSV108879664; COSMIC: COSV108879664;