NM_145199.3(LIPT1):c.292C>G (p.Arg98Gly) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Oct 25, 2022
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001560053.11

Allele description [Variation Report for NM_145199.3(LIPT1):c.292C>G (p.Arg98Gly)]

NM_145199.3(LIPT1):c.292C>G (p.Arg98Gly)

Genes:

LIPT1:lipoyltransferase 1 [Gene - OMIM - HGNC]
MITD1:microtubule interacting and trafficking domain containing 1 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q11.2

Genomic location:

Preferred name:

NM_145199.3(LIPT1):c.292C>G (p.Arg98Gly)

Other names:

LIPT1, ARG98GLY (rs137973334)

HGVS:

NC_000002.12:g.99162249C>G
NG_050665.1:g.12295C>G
NM_001204830.2:c.292C>G
NM_015929.4:c.292C>G
NM_145197.3:c.292C>G
NM_145198.3:c.292C>G
NM_145199.3:c.292C>GMANE SELECT
NP_001191759.1:p.Arg98Gly
NP_057013.1:p.Arg98Gly
NP_660198.1:p.Arg98Gly
NP_660199.1:p.Arg98Gly
NP_660200.1:p.Arg98Gly
NC_000002.11:g.99778712C>G
NM_015929.3:c.292C>G
NR_037935.2:n.777C>G
NR_037936.2:n.441C>G
Q9Y234:p.Arg98Gly

Protein change:

R98G; ARG98GLY

Links:

UniProtKB: Q9Y234#VAR_073670; OMIM: 610284.0004; dbSNP: rs137973334

NCBI 1000 Genomes Browser:

rs137973334

Molecular consequence:

NM_001204830.2:c.292C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_015929.4:c.292C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_145197.3:c.292C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_145198.3:c.292C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_145199.3:c.292C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_037935.2:n.777C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_037936.2:n.441C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001782387	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 12, 2022)	germline	clinical testing	Citation Link,
SCV002251518	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 25, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24256811, 28492532
SCV003802784	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL CNVClassificationCriteria Aug2020)	Likely pathogenic (Aug 5, 2022)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17570395, 24256811, 34440436 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001782387

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Aug 12, 2022)

germline

clinical testing

Citation Link,

SCV002251518

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 25, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV003802784

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL CNVClassificationCriteria Aug2020)

Likely pathogenic
(Aug 5, 2022)

unknown

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Crystal structure of bovine lipoyltransferase in complex with lipoyl-AMP.

Fujiwara K, Hosaka H, Matsuda M, Okamura-Ikeda K, Motokawa Y, Suzuki M, Nakagawa A, Taniguchi H.

J Mol Biol. 2007 Aug 3;371(1):222-34. Epub 2007 May 26.

PubMed [citation]

PMID:: 17570395

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV001782387.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24256811, 29681092, 27247813, 26740555, 28719003, 26633542)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV002251518.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 98 of the LIPT1 protein (p.Arg98Gly). This variant is present in population databases (rs137973334, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of lipoyltransferase 1 deficiency (PMID: 24256811). ClinVar contains an entry for this variant (Variation ID: 189836). 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 LIPT1 protein function. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV003802784.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The LIPT1 c.292C>G (p.Arg98Gly) missense variant results in the substitution of arginine at amino acid position 98 with glycine.The c.292C>G variant is reported in a compound heterozygous state in two affected individuals in the literature, in both instances, in trans with the p.Ser71Phe variant (PMID: 24256811; PMID: 34440436). Normal LIPT1 protein levels are reported in patient liver cells, but 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. Additionally, the Arg98 residue is conserved and structural modelling suggests that it is involved in lipoic acid binding (PMID: 24256811; PMID: 17570395). The c.292C>G variant is reported at a frequency of 0.000241 in the European (non-Finnish) population of the Genome Aggregation Database (version 2.1.1). Based on the available evidence, c.292C>G (p.Arg98Gly) variant is classified as likely pathogenic for lipoyltransferase 1 deficiency.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 4, 2024

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