Submissions for variant NM_000255.4(MMUT):c.1115T>C (p.Ile372Thr)

gnomAD frequency: 0.00050  dbSNP: rs150968643

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000726418	SCV000344506	uncertain significance	not provided	2016-08-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000706536	SCV000463871	uncertain significance	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000726418	SCV000617963	uncertain significance	not provided	2022-06-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000726418	SCV000835593	uncertain significance	not provided	2022-10-13	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 372 of the MUT protein (p.Ile372Thr). This variant is present in population databases (rs150968643, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MUT-related conditions. ClinVar contains an entry for this variant (Variation ID: 290030). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MUT protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000706536	SCV002791314	uncertain significance	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2022-02-09	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001276752	SCV001463280	uncertain significance	Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency	2020-01-09	no assertion criteria provided	clinical testing