NM_004092.4(ECHS1):c.476A>G (p.Gln159Arg) AND Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Sep 30, 2020
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000578268.16

Allele description [Variation Report for NM_004092.4(ECHS1):c.476A>G (p.Gln159Arg)]

NM_004092.4(ECHS1):c.476A>G (p.Gln159Arg)

Gene:

ECHS1:enoyl-CoA hydratase, short chain 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q26.3

Genomic location:

Preferred name:

NM_004092.4(ECHS1):c.476A>G (p.Gln159Arg)

HGVS:

NC_000010.11:g.133368961T>C
NG_042077.1:g.9444A>G
NM_004092.4:c.476A>GMANE SELECT
NP_004083.3:p.Gln159Arg
NC_000010.10:g.135182465T>C
NM_004092.3:c.476A>G

Protein change:

Q159R; GLN159ARG

Links:

OMIM: 602292.0007; dbSNP: rs375032130

NCBI 1000 Genomes Browser:

rs375032130

Molecular consequence:

NM_004092.4:c.476A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency
Synonyms:: PxMD-ECHS1
Identifiers:: MONDO: MONDO:0014563; MedGen: C4225391; Orphanet: 255241; OMIM: 616277

Recent activity

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Talaromyces francoae strain DTO 056D9 calmodulin gene, partial cds
Talaromyces francoae strain DTO 056D9 calmodulin gene, partial cds
gi|1035370728|gb|KX011501.1|

Nucleotide
MZ33314 (0)
Nucleotide
Homologene neighbors for GEO Profiles (Select 98542684) (0)
GEO Profiles
Chromosome neighbors for GEO Profiles (Select 124118372) (19)
GEO Profiles
MAP kinase-interacting serine/threonine-protein kinase 1 isoform X2 [Mus musculu...
MAP kinase-interacting serine/threonine-protein kinase 1 isoform X2 [Mus musculus]
gi|1907154583|ref|XP_036019677.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000680203	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Nov 16, 2017)	germline, paternal	clinical testing	Citation Link,
SCV001244721	Kids Research, The Children's Hospital at Westmead	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	inherited	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 32313153
SCV001244960	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 28, 2018)	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001422319	OMIM	no assertion criteria provided	Pathogenic (Jul 13, 2020)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 26000322, 29575569, 26099313
SCV001441222	Institute of Human Genetics, Cologne University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 30, 2020)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV002024457	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 6, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004042689	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	biparental	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	biparental	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing, research
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	paternal	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	maternal	yes	2	1	not provided	not provided	yes	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The diagnostic utility of genome sequencing in a pediatric cohort with suspected mitochondrial disease.

Riley LG, Cowley MJ, Gayevskiy V, Minoche AE, Puttick C, Thorburn DR, Rius R, Compton AG, Menezes MJ, Bhattacharya K, Coman D, Ellaway C, Alexander IE, Adams L, Kava M, Robinson J, Sue CM, Balasubramaniam S, Christodoulou J.

Genet Med. 2020 Jul;22(7):1254-1261. doi: 10.1038/s41436-020-0793-6. Epub 2020 Apr 21.

PubMed [citation]

PMID:: 32313153

Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement.

Haack TB, Jackson CB, Murayama K, Kremer LS, Schaller A, Kotzaeridou U, de Vries MC, Schottmann G, Santra S, Büchner B, Wieland T, Graf E, Freisinger P, Eggimann S, Ohtake A, Okazaki Y, Kohda M, Kishita Y, Tokuzawa Y, Sauer S, Memari Y, Kolb-Kokocinski A, et al.

Ann Clin Transl Neurol. 2015 May;2(5):492-509. doi: 10.1002/acn3.189. Epub 2015 Mar 13.

PubMed [citation]

PMID:: 26000322
PMCID:: PMC4435704

See all PubMed Citations (5)

Details of each submission

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV000680203.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided
2	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
2	paternal	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Kids Research, The Children's Hospital at Westmead, SCV001244721.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV001244960.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	yes	clinical testing	PubMed (1)

Description

A heterozygous missense variant, NM_004092.3(ECHS1):c.476A>G, has been identified in exon 4 of 8 of the ECHS1 gene. The variant is predicted to result in a moderate amino acid change from glutamine to arginine at position 159 of the protein (NP_004083.3(ECHS1):p.(Gln159Arg)). The glutamine residue at this position has very high conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. The variant is present in the gnomAD database at a frequency of 0.01% (29 heterozygotes, 0 homozygotes). The variant has previously been reported as likely pathogenic in ClinVar and is reported multiple times in the liteature in patients with deficiency of shortchain enoyl-CoA hydratase (Ganetzky RD et al., 2016, Haack TB et al.; 2015, Tetreault M et al., 2015, Ferdinandusse S et al.; 2015). One of these reports showed significantly reduced enzymatic activity in a patient that was compound heterozygous for this variant (Ferdinandusse S et al.; 2015). Analysis of parental samples indicated this variant was maternally inherited. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	not provided	not provided		2	not provided	1	not provided

From OMIM, SCV001422319.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

In 3 sibs (proband 68552) with mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D; 616277), who were born to consanguineous Pakistani parents (family 3), Haack et al. (2015) identified a homozygous c.476A-G transition (c.476A-G, NM_004092.3) in exon 4 of the ECHS1 gene, resulting in a gln159-to-arg (Q159R) substitution. The mutation was identified by whole-exome sequencing in 1 sib and confirmed by Sanger sequencing from blood spots in the 2 other sibs (identical female twins), who were deceased. The parents were heterozygous for the mutation. Haack et al. (2015) identified the Q159R mutation in compound heterozygosity with different ECHS1 mutations in 2 unrelated patients with ECHS1D: patient 346 (family 1) had the previously identified N9S mutation (602292.0005) and patient 52236 (family 10) had a c.229G-C transversion, resulting in a glu77-to-gln (E77Q; 602292.0009) substitution. Immunoblot analysis on fibroblasts from patients 346 and 52236 showed reduced expression of the ECHS1 protein; reduced palmitate-dependent respiration and reduced 2-enoyl-CoA hydratase activity was found in the fibroblasts of patient 52236. The Q159R variant had an allele frequency of 0.0001148 in the ExAC database, and the E77Q was not present in the database.

In 3 Irish Traveler sibs with ECHS1D, Fitzsimons et al. (2018) identified homozygosity for the Q159R mutation in the ECHS1 gene. Erythro-2,3-dihydroxy-2-methylbutyrate and 3-methylglutaconic acid were elevated on urine organic acids of all patients. Muscle and fibroblast testing was carried out in 1 sib. Fibroblasts showed markedly decreased ECHS1 enzyme activity and absence of ECHS1 on Western blot analysis. PDH activity and beta oxidation studies were normal. Activities of respiratory chain complexes I, II, and IV were normal, and activity of complexes II+III was decreased in muscle.

For discussion of the Q159R mutation in the ESCHS1 gene that was found in compound heterozygosity in a patient (P4) with ESCHS1D by Tetreault et al. (2015), see 602292.0009.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, Cologne University, SCV001441222.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002024457.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV004042689.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	biparental	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Aug 4, 2024

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