Submissions for variant NM_004092.4(ECHS1):c.830C>T (p.Thr277Ile)

gnomAD frequency: 0.00001  dbSNP: rs775650144

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000449543	SCV000537753	likely pathogenic	Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency	2016-09-21	criteria provided, single submitter	clinical testing	This heterozygous variant in the ECHS1 gene (autosomal recessive transmission) is present in a female patient who also harbours a large deletion in the same gene (see below)(compound heterozygosity). Following the recommendations of Richards et al. (2015), this variant is classified as a VUS. However, regarding the accordance with the clinical features of the patient due to its combination with the second variant in the ECHS1 gene, this variant was reclassified as a class 4 variant (probably pathogenic).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000449543	SCV002768706	likely pathogenic	Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from threonine to isoleucine (exon 8). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes). (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif (Enoyl-CoA hydratase/isomerase: PDB, NCBI). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0803 - Low previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported as likely pathogenic in two patients (ClinVar, VCGS). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant in a recessive disease. (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign