rs150321966

Positions:

• chr10-133366990-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_004092.4(ECHS1):​c.518C>T​(p.Ala173Val) variant causes a missense change. The variant allele was found at a frequency of 0.000176 in 1,609,246 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A173A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: ECHS1 NM_004092.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 U:1 O:1
• Conservation: PhyloP100: 4.80

Genes affected

ECHS1 (HGNC:3151): (enoyl-CoA hydratase, short chain 1) The protein encoded by this gene functions in the second step of the mitochondrial fatty acid beta-oxidation pathway. It catalyzes the hydration of 2-trans-enoyl-coenzyme A (CoA) intermediates to L-3-hydroxyacyl-CoAs. The gene product is a member of the hydratase/isomerase superfamily. It localizes to the mitochondrial matrix. Transcript variants utilizing alternative transcription initiation sites have been described in the literature. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_004092.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-133366990-G-A is Pathogenic according to our data. Variant chr10-133366990-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 377257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ECHS1	NM_004092.4	c.518C>T	p.Ala173Val	missense_variant	5/8	ENST00000368547.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECHS1	ENST00000368547.4	c.518C>T	p.Ala173Val	missense_variant	5/8	1	NM_004092.4	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152238 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000261 AC: 64 AN: 245094 Hom.: 0 AF XY: 0.000308 AC XY: 41 AN XY: 133022

Gnomad AFR exome AF: 0.000252

Gnomad AMR exome AF: 0.0000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000133

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000469

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000181 AC: 264 AN: 1457008 Hom.: 1 Cov.: 33 AF XY: 0.000197 AC XY: 143 AN XY: 724778

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.0000673

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.0000392

Gnomad4 NFE exome AF: 0.000208

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152238 Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 12 AN XY: 74376

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000287 Hom.: 0

Bravo AF: 0.000151

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000363 AC: 44

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency Pathogenic:6 Uncertain:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed missense variant c.518C>T(p.Ala173Val) in ECHS1 gene has been reported previously in compound heterozygous state in multiple individuals with ECHS1-related conditions (Illsinger S, et al., 2020, Olgiati S, et al., 2016). This variant is reported to being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. The c.518C>T variant has 0.02% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic/Uncertain Significance. Multiple lines of computational evidence (Polyphen, SIFT and MutationTaster) predict a damaging effect on protein structure and function for this variant. The amino acid Alanine at position 173 is changed to a Valine changing protein sequence and it might alter its composition and physico-chemical properties.The amino acid change p.Ala173Val in ECHS1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 15, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, flagged submission	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 23, 2022	ACMG classification criteria: PM3 very strong, PP1 supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 05, 2017	Two heterozygous variants were identified in the ECHS1 gene, NM_004092.3(ECHS1):c.518C>T and NM_004092.3(ECHS1):c.541C>T. The NM_004092.3(ECHS1):c.518C>T missense variant is in exon 5 of the ECHS1 gene (chr10:135180494). This substitution is predicted to create a change of an alanine to a valine at amino acid position 173, NP_004083.3(ECHS1):p.(Ala173Val), which is NOT considered significant. The alanine at this position has low conservation and therefore Grantham assessment (A-GVGD) is unlikely pathogenic. In silico software predictions of the pathogenicity of this variant are conflicting. It is situated within a known functional region (conserved trimeric quaternary structure which contains the catalytic core). This variant has not been previously observed in our patient cohort but it has been observed in a population database at a frequency of 0.04% (ExAC). It has been previously reported in a compound heterozygous state in three individuals presenting with later-onset movement disorders (Olgiati et al 2016, Mahajan et al 2017). Additional biochemical evaluation in this patient was consistent with ECHS1 deficiency. Based on current information and biochemical evidence, this variant has been classified as LIKELY PATHOGENIC. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 16, 2017	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	ECHS1: PM3:Strong, PM2, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2023	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) -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.40
Sift	Benign	0.034	D
Sift4G	Uncertain	0.037	D
Polyphen		0.93	P
Vest4		0.63
MVP		0.59
MPC		1.3
ClinPred		0.52	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs150321966; hg19: chr10-135180494;