rs1554400699

Positions:

• chr7-107919054-TG-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000108.5(DLD):​c.1421del​(p.Gly474GlufsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G474G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DLD NM_000108.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.60

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-107919054-TG-T is Pathogenic according to our data. Variant chr7-107919054-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555593.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLD	NM_000108.5	c.1421del	p.Gly474GlufsTer7	frameshift_variant	13/14	ENST00000205402.10
DLD	NM_001289751.1	c.1352del	p.Gly451GlufsTer7	frameshift_variant	12/13
DLD	NM_001289752.1	c.1277del	p.Gly426GlufsTer7	frameshift_variant	12/13
DLD	NM_001289750.1	c.1124del	p.Gly375GlufsTer7	frameshift_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLD	ENST00000205402.10	c.1421del	p.Gly474GlufsTer7	frameshift_variant	13/14	1	NM_000108.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pyruvate dehydrogenase E3 deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Dec 13, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1554400699; hg19: chr7-107559499;