Submissions for variant NM_004826.4(ECEL1):c.1470G>A (p.Trp490Ter)

gnomAD frequency: 0.00011  dbSNP: rs149459910

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000627254	SCV000748246	pathogenic	not provided	2022-09-09	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27959697, 33491998, 23236030, 30131190, 31127727, 33101984, 33672664)
Pathology and Clinical Laboratory Medicine, King Fahad Medical City	RCV000414781	SCV001438953	pathogenic	Distal arthrogryposis type 5D		criteria provided, single submitter	clinical testing
DASA	RCV000414781	SCV002061226	pathogenic	Distal arthrogryposis type 5D	2022-01-05	criteria provided, single submitter	clinical testing	The c.1470G>A;p.(Trp490*) variant creates a premature translational stop signal in the ECEL1 gene. It is expected to result in an absent or disrupted protein product - PVS1.This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(ClinVar ID: 374305; PMID: 23236030) - PS4_moderate. The variant is present at low allele frequencies population databases (rs149459910 – gnomAD 0.01117%; ABraOM no frequency- http://abraom.ib.usp.br/) -PM2_supporting. The p.(Trp490*) was detected in trans with a pathogenic variant (PMID: 23236030) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252117	SCV002523981	pathogenic	See cases	2019-06-11	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PM1, PP5, BS1
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000414781	SCV003800057	pathogenic	Distal arthrogryposis type 5D	2022-09-14	criteria provided, single submitter	clinical testing	The ECEL1 c.1470G>A; p.Trp490Ter variant (rs149459910) is reported in the literature in the compound heterozygous and homozygous states in individuals with distal arthrogryposis (AlBanji 2020, Dieterich 2013, Posey 2017). This variant is found in the African/African-American population with an allele frequency of 0.048% (12/24910 alleles) in the Genome Aggregation Database ; it is also reported in ClinVar (Variation ID: 374305). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: AlBanji MH et al. Utility of Hypotonia Diagnostic Investigations: A 12-year Single Center Study. Mol Genet Metab Rep. 2020 Oct 21;25:100665. PMID: 33101984 Dieterich K et al. The neuronal endopeptidase ECEL1 is associated with a distinct form of recessive distal arthrogryposis. Hum Mol Genet. 2013 Apr 15;22(8):1483-92. PMID: 23236030. Posey JE et al. Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. N Engl J Med. 2017 Jan 5;376(1):21-31. PMID: 27959697
Molecular Genetics Lab, CHRU Brest	RCV000414781	SCV004697614	pathogenic	Distal arthrogryposis type 5D		criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000414781	SCV004804950	pathogenic	Distal arthrogryposis type 5D	2024-03-17	criteria provided, single submitter	research
Baylor Genetics	RCV000414781	SCV000328781	pathogenic	Distal arthrogryposis type 5D	2014-09-29	no assertion criteria provided	clinical testing	Our laboratory reported dual molecular diagnoses in ARHGEF10 (NM_014629.2, c.1456dup and c.2063G>A in trans) and ECEL1 (NM_004826.2, c.1470G>A) in this individual reported to have features of delayed motor milestones, dysmorphic features, joint contracture at elbow, knee and small joints and camptodactyly. Compound heterozygous pathogenic variants including c.1470G>A (p.W490X) have been previously reported in a patient with recessive form of distal arthrogryposis (PMID 23236030). Heterozygotes for this variant would be expected to be asymptomatic carriers.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000414781	SCV001190789	pathogenic	Distal arthrogryposis type 5D	2020-02-05	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000627254	SCV001807429	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000627254	SCV001951286	pathogenic	not provided		no assertion criteria provided	clinical testing