rs28940289

Variant names:

• chr19-43511455-G-A
• rs28940289
• NM_014297.5:c.487C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-43511455-G-A
• chr19-43511455-G-C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PP4_Moderate PM3_Strong PP1_Strong PS3_Supporting PM5 PP3

This summary comes from the ClinGen Evidence Repository: The ETHE1 c.487C>T mutation is a missense mutation at the 163 amino acid position where one other pathogenic mutation has been reported (c.488G>A) indicating that this residue is critical to the function of the protein (PM5_moderate). There are multiple lines of computational evidence supporting a deleterious effect (PP3_supporting). Functional studies performed in ETHE1 isolated from E-coli cells demonstrated 10 fold reduced ETHE1 catalytic activity when compared to controls (PS3_supporting; PMID:25198162). The c.487C>T mutation has been reported in four unrelated affected individuals including three who were homozygous for the mutation (PMID:16183799; PMID:16828325; PMID:28698729) and one proband where the c. 487C>T was found in trans with another reportedly pathogenic ETHE1 mutation (PMID:18593870) (PM3_strong). One of these patients demonstrated a clinical phenotype specific to ethylmalonic encephalopathy including chronic diarrhea, petechiae, acrocyanosis, and developmental delay in addition to the biochemical findings urinary ethylmalonic acid and elevated blood C4-acylcarnitine esters and blood C5-acylcarnitines (PP4_moderate; PMID:16828325). A larger family including 7 children has been reported where homozygous c.487C>T mutation was identified in the three affected siblings and segregated with disease in the unaffected siblings (PP1_strong; PMID:14732903). In summary, this variant meets criteria to be classified as pathogenic for ethylmalonic encephalopathy in an autosomal recessive manner. ETHE1-specific ACMG/AMP criteria applied PM5_moderate; PP3_supporting; PS3_supporting; PM3_strong; PP4_moderate; PP1_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA115479/MONDO:0011229/014

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ETHE1 NM_014297.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:10 O:1
• Conservation: PhyloP100: 3.98
• Publications: 21 publications found

Genes affected

ETHE1 (HGNC:23287): (ETHE1 persulfide dioxygenase) This gene encodes a member of the metallo beta-lactamase family of iron-containing proteins involved in the mitochondrial sulfide oxidation pathway. The encoded protein catalyzes the oxidation of a persulfide substrate to sulfite. Certain mutations in this gene cause ethylmalonic encephalopathy, an infantile metabolic disorder affecting the brain, gastrointestinal tract and peripheral vessels. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

ETHE1 Gene-Disease associations (from GenCC):

• ethylmalonic encephalopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014297.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETHE1	NM_014297.5	MANE Select	c.487C>T	p.Arg163Trp	missense	Exon 4 of 7	NP_055112.2
	ETHE1	NM_001320867.2		c.454C>T	p.Arg152Trp	missense	Exon 4 of 7	NP_001307796.1
	ETHE1	NM_001320869.2		c.193C>T	p.Arg65Trp	missense	Exon 2 of 5	NP_001307798.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETHE1	ENST00000292147.7	TSL:1 MANE Select	c.487C>T	p.Arg163Trp	missense	Exon 4 of 7	ENSP00000292147.1
	ETHE1	ENST00000600651.5	TSL:1	c.487C>T	p.Arg163Trp	missense	Exon 4 of 6	ENSP00000469037.1
	ETHE1	ENST00000880125.1		c.652C>T	p.Arg218Trp	missense	Exon 5 of 8	ENSP00000550184.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251460 AF XY: 0.0000147

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727238

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111992

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

African (AFR) AF: 0.0000483 AC: 2 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00000477 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	-	-	Ethylmalonic encephalopathy (10)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		4.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.95
gMVP		0.95
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs28940289; hg19: chr19-44015607;