Submissions for variant NM_004092.4(ECHS1):c.489G>A (p.Pro163=)

gnomAD frequency: 0.00042  dbSNP: rs140410716

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000427574	SCV000526153	likely benign	not specified	2016-03-31	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000894199	SCV001038169	benign	not provided	2024-01-28	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272235	SCV002557147	uncertain significance	Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (MIM#616277). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). This synonymous variant reportedly affects splicing, however functional studies are inconclusive (PMID: 33112498). (I) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD (v2) >=0.01 and <0.03 for a recessive condition (256 heterozygotes, 2 homozygotes). In addition, this variant has a minor allele frequency of 0.17 in the Samoan population with 54 homozygotes reported (PMID: 33112498). (I) 0506 - Abnormal splicing is not predicted and nucleotide is poorly conserved. (SB) 0705 - No comparable variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as benign and likely benign in ClinVar, however it has been thought to be a hypomorphic allele contributing to disease in two families with Samoan decent (PMIDs: 32642440, 33112498). (I) 0906 - Segregation evidence for this variant is inconclusive. It was identified in two families in compound heterozygote affected individuals, however it was also reported in an unaffected mother who was homozygote (PMIDs: 32642440, 33112498). (I) 1010 - Functional evidence for this variant is inconclusive. The studies were performed using fibroblasts and no site-directed mutagenesis experiments were conducted. In addition, no impact in splicing was detected (PMID: 33112498). (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV002272235	SCV002808878	likely benign	Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency	2022-03-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003922780	SCV004737497	likely benign	ECHS1-related disorder	2019-09-23	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
OMIM	RCV002272235	SCV005184173	pathogenic	Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency	2024-08-06	no assertion criteria provided	literature only