7-107915506-G-T

Position:

• chr7-107915506-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000108.5(DLD):​c.685G>T​(p.Gly229Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,613,460 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: DLD NM_000108.5 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:22
• Conservation: PhyloP100: 10.0

Genes affected

DLD (HGNC:2898): (dihydrolipoamide dehydrogenase) This gene encodes a member of the class-I pyridine nucleotide-disulfide oxidoreductase family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. In homodimeric form, the encoded protein functions as a dehydrogenase and is found in several multi-enzyme complexes that regulate energy metabolism. However, as a monomer, this protein can function as a protease. Mutations in this gene have been identified in patients with E3-deficient maple syrup urine disease and lipoamide dehydrogenase deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 7-107915506-G-T is Pathogenic according to our data. Variant chr7-107915506-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 11966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107915506-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLD	NM_000108.5	c.685G>T	p.Gly229Cys	missense_variant, splice_region_variant	9/14	ENST00000205402.10	NP_000099.2
DLD	NM_001289751.1	c.616G>T	p.Gly206Cys	missense_variant, splice_region_variant	8/13		NP_001276680.1
DLD	NM_001289752.1	c.541G>T	p.Gly181Cys	missense_variant, splice_region_variant	8/13		NP_001276681.1
DLD	NM_001289750.1	c.388G>T	p.Gly130Cys	missense_variant, splice_region_variant	7/12		NP_001276679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLD	ENST00000205402.10	c.685G>T	p.Gly229Cys	missense_variant, splice_region_variant	9/14	1	NM_000108.5	ENSP00000205402	P1

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 152028 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000326 AC: 82 AN: 251208 Hom.: 1 AF XY: 0.000346 AC XY: 47 AN XY: 135772

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00626

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000135 AC: 198 AN: 1461432 Hom.: 0 Cov.: 31 AF XY: 0.000140 AC XY: 102 AN XY: 727018

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00482

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000178 AC: 27 AN: 152028 Hom.: 1 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74266

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000319 Hom.: 0

Bravo AF: 0.000162

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000264 AC: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyruvate dehydrogenase E3 deficiency Pathogenic:15

Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Jun 04, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 06, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2011	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000108.3:c.685G>T in the DLD gene has an allele frequency of 0.007 in Ashkenazi Jewish subpopulation in the gnomAD database. Haviv R et al. reported that eight of 15 studied patients with dihydrolipoamide dehydrogenase deficiency were homozygous for the common G229C mutation and two were compound heterozygous for the G229C and Y35X mutations (PMID: 23995961). Functional studies using biochemical and biophysical analyses demonstrated that the variant increases the generation of reactive oxygen species compared to the wild type enzyme (PMID: 21558426). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3_Strong; PS3; PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 27, 2016	Variant summary: The DLD c.685G>T (p.Gly229Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 32/121202 control chromosomes (1 homozygote) at a frequency of 0.000264, which does not exceed the estimated maximal expected allele frequency of a pathogenic DLD variant (0.005). The variant has been reported in numerous affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 229 of the DLD protein (p.Gly229Cys). This variant is present in population databases (rs121964990, gnomAD 0.6%). This missense change has been observed in individuals with dihydrolipoamide dehydrogenase deficiency (PMID: 21558426, 21930696, 23478190). It has also been observed to segregate with disease in related individuals. This variant is also known as Gly194Cys. ClinVar contains an entry for this variant (Variation ID: 11966). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects DLD function (PMID: 21558426, 21930696). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 18, 2019	NM_000108.3(DLD):c.685G>T(G229C, aka G194C) is classified as pathogenic in the context of dihydrolipoamide dehydrogenase deficiency. Sources cited for classification include the following: PMIDs: 16601893, 14765544, 23995961, 21930696, 21558426, 9934985. Classification of NM_000108.3(DLD):c.685G>T(G229C, aka G194C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	GeneReviews	Apr 02, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Apr 12, 2020	This variant was previously reported in patients with dihydrolipoamide dehydrogenase (DLD or E3) deficiency in homozygous and compound heterozygous state. In addition, this variant was also identified in a heterozygous state without a second variant [PMID's: 9934985, 23478190, 23995961] and reported as disease causing mutation located in NAD+ binding domain [PMID: 23478190]. This variant in the DLD gene has been reported with a carrier frequency of 1 in 94 in the Ashkenazi Jewish population [PMID: 9934985]. Functional studies on this variant p.Gly229Cys (represented as G194C) have shown to impairs DLD function and results in increased reactive oxygen species (ROS) generation in vitro and in yeast [PMID: 21558426, 21930696]. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 30, 2023	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2024	Reported carrier frequency of 1 in 94 in the Ashkenazi Jewish population (PMID: 9934985); Functional studies of the p.(G229C) variant showed a decrease in the mitochondrial respiratory function relative to wild-type (PMID: 21930696); 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: 24012808, 25333069, 25885067, 9934985, 20672374, 17404228, 10448086, 8968745, 30487145, 34745891, 35379322, 21558426, 25356417, 23995961, 27544700, 37701333, 16601893, 14765544, 24516753, 16770810, 15712224, 12925875, 9764998, 30264509, 23290025, 23478190, 31334547, 31980526, 31589614, 33083013, 32778825, 34023347, 21930696) -

DLD-related disorder Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 21, 2024	The DLD c.685G>T variant is predicted to result in the amino acid substitution p.Gly229Cys. This variant has been reported to be causative for dihydrolipoamide dehydrogenase deficiency and is commonly found in individuals with Ashkenazi Jewish or Arab ancestry (see for example, Shaag et al., 1999. PubMed ID: 9934985; Brassier et al. 2013. PubMed ID: 23478190). This variant is reported in 0.66% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	Across a selection of available literature, the DLD c.685G>T (p.Gly229Cys) missense variant has been identified in a total of 27 patients with dihydrolipoamide dehydrogenase deficiency (also known as maple syrup urine disease type III), including 22 in a homozygous state, four in a compound heterozygous state, and one in a heterozygous state in whom a second variant was not identified (Shaag et al. 1999; Brassier et al. 2013; Haviv et al. 2014). The p.Gly229Cys variant was also identified in a heterozygous state in five unaffected family members. Control data are not available for this variant, which is reported at a frequency of 0.00042 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.Gly229Cys variant is located in the NAD+ binding domain of the protein. Functional studies using biochemical and biophysical analyses demonstrated that the variant increases the generation of reactive oxygen species compared to the wild type enzyme (Ambrus et al. 2011). Based on the evidence, the p.Gly229Cys variant is classified as pathogenic for DLD-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.685G>T;p.(Gly229Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 11966; PMID: 21930696; 23478190; 21558426; OMIM: 238331.0006) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 23478190, 21558426, 21930696) - PS3_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (NAD + binding) - PM1. The variant is present at low allele frequencies population databases (rs121964990– gnomAD 0.001776%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Gly229Cys) was detected in trans with a pathogenic variant (PMID: 23995961) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	3.8	H;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-8.5	D;D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.97
MVP		0.91
MPC		0.80
ClinPred		0.64	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.020		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: rs121964990; hg19: chr7-107555951;