NM_000108.5(DLD):c.1058T>C (p.Ile353Thr) AND Pyruvate dehydrogenase E3 deficiency

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 2, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV002032886.9

Allele description [Variation Report for NM_000108.5(DLD):c.1058T>C (p.Ile353Thr)]

NM_000108.5(DLD):c.1058T>C (p.Ile353Thr)

Gene:

DLD:dihydrolipoamide dehydrogenase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.1

Genomic location:

Preferred name:

NM_000108.5(DLD):c.1058T>C (p.Ile353Thr)

HGVS:

NC_000007.14:g.107917284T>C
NG_008045.1:g.31144T>C
NM_000108.4:c.1058T>C
NM_000108.5:c.1058T>CMANE SELECT
NM_001289750.1:c.761T>C
NM_001289751.1:c.989T>C
NM_001289752.1:c.914T>C
NP_000099.2:p.Ile353Thr
NP_001276679.1:p.Ile254Thr
NP_001276680.1:p.Ile330Thr
NP_001276681.1:p.Ile305Thr
NC_000007.13:g.107557729T>C
NM_000108.5:c.1058T>C

Protein change:

I254T

Links:

dbSNP: rs2116271469

NCBI 1000 Genomes Browser:

rs2116271469

Molecular consequence:

NM_000108.5:c.1058T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001289750.1:c.761T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001289751.1:c.989T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001289752.1:c.914T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Pyruvate dehydrogenase E3 deficiency (DLDD)
Synonyms:: MAPLE SYRUP URINE DISEASE, TYPE III; DIHYDROLIPOAMIDE DEHYDROGENASE DEFICIENCY; Maple syrup urine disease, type 3; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009529; MedGen: C5574660; Orphanet: 2394; Orphanet: 765; OMIM: 246900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002111941	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 21, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23290025, 27896107, 33306821, 28492532
SCV003928786	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 28, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23290025, 27896107, 34684524, 33306821 Citation Link,
SCV004193958	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 2, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002111941

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 21, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV003928786

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Apr 28, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV004193958

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 2, 2024)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

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	unknown	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

Leigh syndrome in a girl with a novel DLD mutation causing E3 deficiency.

Quinonez SC, Leber SM, Martin DM, Thoene JG, Bedoyan JK.

Pediatr Neurol. 2013 Jan;48(1):67-72. doi: 10.1016/j.pediatrneurol.2012.09.013.

PubMed [citation]

PMID:: 23290025
PMCID:: PMC4535688

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002111941.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 353 of the DLD protein (p.Ile353Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dihydrolipoamide dehydrogenase deficiency (PMID: 23290025, 27896107, 33306821). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as I318T. ClinVar contains an entry for this variant (Variation ID: 1346904). 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 DLD protein function. For these reasons, this variant has been classified as Pathogenic.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003928786.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: DLD c.1058T>C (p.Ile353Thr) results in a non-conservative amino acid change located in the FAD/NAD(P)-binding domain (IPR023753) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251324 control chromosomes. c.1058T>C has been reported in the literature as a biallelic compound heterozygous genotype in individuals affected with Dihydrolipoamide Dehydrogenase Deficiency (MSUD Type 3) (example, Quinonez_2014, Quinonez_2013, Wu_2020, Staretz-Chacham_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27896107, 23290025, 34684524, 33306821). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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 Baylor Genetics, SCV004193958.2

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

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

Last Updated: Sep 29, 2024

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