Submissions for variant NM_000016.6(ACADM):c.1247T>C (p.Ile416Thr)

gnomAD frequency: 0.00006  dbSNP: rs760892123

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185669	SCV000238588	uncertain significance	not provided	2017-01-19	criteria provided, single submitter	clinical testing	The I416T missense change in the ACADM gene has not been reported as a benign polymorphism. It has been reported previously in three patients detected by positive newborn screening results for medium chain acyl-CoA dehydrogenase (MCAD) deficiency who also harbored the K329E mutation (Smith et al., 2010 Couce et al., 2011). Biochemical analyses on these patients and in-silico analysis of I416T led the authors to conclude that this missense change was a variant of unknown significance. I416T is a non-conservative amino acid change in that a non-polar Isoleucine residue is replaced by a polar Threonine residue. This change occurs at a position that is highly conserved in the ACADM protein in mammals; however, this position is not highly conserved outside mammals or in related proteins. Multiple in-silico analysis models predict that I416T is a benign sequence change. Therefore, based on the currently available information, it is unclear whether I416T is a disease-causing mutation or a rare benign variant. The variant is found in ACADM panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000556896	SCV000630278	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 416 of the ACADM protein (p.Ile416Thr). This variant is present in population databases (rs760892123, gnomAD 0.006%). This missense change has been observed in individual(s) with mildly elevated levels of C8 and MCAD deficiency (PMID: 20434380, 23430840, 26947917; Invitae). ClinVar contains an entry for this variant (Variation ID: 203543). 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 expected to disrupt ACADM protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect ACADM function (PMID: 26947917). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000556896	SCV000798902	uncertain significance	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2018-03-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804919	SCV002050774	uncertain significance	not specified	2021-12-06	criteria provided, single submitter	clinical testing	Variant summary: ACADM c.1247T>C (p.Ile416Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 249404 control chromosomes (gnomAD), however the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1247T>C has been reported in the literature in newborns and other individuals suspected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (example: Smith_2010, Couce_2011, Couce_2013, Hara_2016, Tajima_2016, Adhikari_2020), but these data do not allow any conclusion about variant significance. Experimental evidence evaluating an impact on protein function demonstrated the variant has near normal residual enzymatic activity and thermal stability (Hara_2016). Three ClinVar submitters have assessed this variant since 2014: two have classified this variant as uncertain significance and one has classified it as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252028	SCV002523342	uncertain significance	See cases	2019-11-13	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3, PS4, PM2