NM_004092.4(ECHS1):c.518C>T (p.Ala173Val) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Oct 3, 2024
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:: RCV000421257.28

Allele description [Variation Report for NM_004092.4(ECHS1):c.518C>T (p.Ala173Val)]

NM_004092.4(ECHS1):c.518C>T (p.Ala173Val)

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.518C>T (p.Ala173Val)

HGVS:

NC_000010.11:g.133366990G>A
NG_042077.1:g.11415C>T
NM_004092.4:c.518C>TMANE SELECT
NP_004083.3:p.Ala173Val
NC_000010.10:g.135180494G>A
NM_004092.3:c.518C>T

Protein change:

A173V

Links:

dbSNP: rs150321966

NCBI 1000 Genomes Browser:

rs150321966

Molecular consequence:

NM_004092.4:c.518C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000511597	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 1, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001771007	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 3, 2024)	germline	clinical testing	Citation Link,
SCV002243598	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 27090768, 28039521, 30008475, 32677093, 32858208, 28492532
SCV004010030	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely pathogenic (Apr 1, 2023)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	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	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Paroxysmal exercise-induced dystonia within the phenotypic spectrum of ECHS1 deficiency.

Olgiati S, Skorvanek M, Quadri M, Minneboo M, Graafland J, Breedveld GJ, Bonte R, Ozgur Z, van den Hout MC, Schoonderwoerd K, Verheijen FW, van IJcken WF, Chien HF, Barbosa ER, Chang HC, Lai SC, Yeh TH, Lu CS, Wu-Chou YH, Kievit AJ, Han V, Gdovinova Z, et al.

Mov Disord. 2016 Jul;31(7):1041-8. doi: 10.1002/mds.26610. Epub 2016 Apr 19.

PubMed [citation]

PMID:: 27090768

See all PubMed Citations (7)

Details of each submission

From Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000511597.1

#	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	not provided	not provided	not provided	not provided		not provided	0.001043	not provided	not provided

From GeneDx, SCV001771007.7

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31219693, 33931985, 32777769, 30008475, 28039521, 27090768, 29882869, 26099313, 31628766, 32858208, 33929620, 34140924, 34716721, 32677093, 33258288, 35856138, 35206276, 34052969, Das_2022_Abstract, 36200804, 35394834, 36883047, 33688149)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002243598.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 173 of the ECHS1 protein (p.Ala173Val). This variant is present in population databases (rs150321966, gnomAD 0.04%). This missense change has been observed in individual(s) with ECHS1-related conditions (PMID: 27090768, 28039521, 30008475, 32677093, 32858208). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 377257). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ECHS1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

#	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 CeGaT Center for Human Genetics Tuebingen, SCV004010030.13

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

Description

ECHS1: PM3:Strong, PM2, PP1

#	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

Last Updated: Dec 22, 2024

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