rs796051962

chr4-158682314-C-CGT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004453.4(ETFDH):c.302_303dup(p.Leu102ValfsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ETFDH NM_004453.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 10.0

Genes affected

ETFDH (HGNC:3483): (electron transfer flavoprotein dehydrogenase) This gene encodes a component of the electron-transfer system in mitochondria and is essential for electron transfer from a number of mitochondrial flavin-containing dehydrogenases to the main respiratory chain. Mutations in this gene are associated with glutaric acidemia. Alternatively spliced transcript variants that encode distinct isoforms have been observed. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-158682314-C-CGT is Pathogenic according to our data. Variant chr4-158682314-C-CGT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ETFDH	NM_004453.4	c.302_303dup	p.Leu102ValfsTer2	frameshift_variant	3/13	ENST00000511912.6
ETFDH	NM_001281737.2	c.161_162dup	p.Leu55ValfsTer2	frameshift_variant	2/12
ETFDH	NM_001281738.1	c.119_120dup	p.Leu41ValfsTer2	frameshift_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ETFDH	ENST00000511912.6	c.302_303dup	p.Leu102ValfsTer2	frameshift_variant	3/13	1	NM_004453.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 21, 2023	This sequence change creates a premature translational stop signal (p.Leu102Valfs*2) in the ETFDH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ETFDH are known to be pathogenic (PMID: 16510302, 23785301). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ETFDH-related conditions. ClinVar contains an entry for this variant (Variation ID: 203727). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 26, 2023	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 17, 2013

The c.302_303dupGT, the normal sequence with the bases that are duplicated in braces is CGTGTGT[GT]CTAGT. The mutation causes a frameshift starting with codon Leucine 102, changes this amino acid to a Valine residue and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Leu102ValfsX2. This mutation is predicted to cause loss of normal protein function through protein truncation. Although this mutation has not been previously reported to our knowledge, it is expected to be a pathogenic mutation. The variant is found in ETFDH panel(s). -

ETFDH-related condition Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 30, 2023

The ETFDH c.302_303dupGT variant is predicted to result in a frameshift and premature protein termination (p.Leu102Valfs*2). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in ETFDH are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs796051962; hg19: chr4-159603466;