6-127327143-ACCTGC-TA

Variant summary

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

The NM_001002030.2(ECHDC1):c.221-4_222delinsTA variant causes a splice acceptor, coding sequence, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ECHDC1 NM_001002030.2 splice_acceptor, coding_sequence, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.32

Genes affected

ECHDC1 (HGNC:21489): (ethylmalonyl-CoA decarboxylase 1) Predicted to enable carboxy-lyase activity and enoyl-CoA hydratase activity. Predicted to be involved in fatty acid beta-oxidation. Predicted to be integral component of membrane. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

LOC105377994 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.15673289 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.9, offset of 3, new splice context is: tcccacttccatctctgtAGtta. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-127327143-ACCTGC-TA is Pathogenic according to our data. Variant chr6-127327143-ACCTGC-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 978062.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ECHDC1	NM_001002030.2	c.221-4_222delinsTA		splice_acceptor_variant, coding_sequence_variant, intron_variant	3/6	ENST00000454859.8
LOC105377994	XR_001744333.2	n.8292+1867_8292+1872delinsTA		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECHDC1	ENST00000454859.8	c.221-4_222delinsTA		splice_acceptor_variant, coding_sequence_variant, intron_variant	3/6	1	NM_001002030.2	P2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Research Unit for Molecular Medicine, Department for Clinical Medicine, Aarhus University

Sep 12, 2019

ECHDC1 encodes a 'metabolite repair enzyme' detoxifying ethylmalonic acid (EMA), which is the biochemical hallmark of short-chain acyl-CoA dehydrogenase deficiency (OMIM:201470), caused by biallelic ACADS variants. We provide functional evidence that ECHDC1 c.221-4_222delinTA is a loss-of function (LOF) variant. The variant was identified in the heterozygous state together with a homozygous ACADS NM_000017.2:c.625G>A susceptibility variant. We provide functional evidence that ECHDC1 haploinsufficiency in combination with ACADS c.625G>A susceptibility variants has a synergistic effect on cellular EMA levels. In a cohort of 82 genetically unsolved EMA patients, we found three unrelated cases with heterozygous LOF ECHDC1 variants combined with ACADS c.625G>A suceptibility variants. -

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: rs1783424526; hg19: chr6-127648288;