Submissions for variant NM_000255.4(MMUT):c.322C>T (p.Arg108Cys)

gnomAD frequency: 0.00001  dbSNP: rs121918257

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000001964	SCV000595872	pathogenic	METHYLMALONIC ACIDURIA, mut(0) TYPE	2016-04-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001376644	SCV000641779	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 108 of the MUT protein (p.Arg108Cys). This variant is present in population databases (rs121918257, gnomAD 0.08%). This missense change has been observed in individual(s) with methylmalonic acidemia (PMID: 2661559, 16281286, 17075691, 22614770, 23045948, 24059531, 24464670, 27578510). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1887). 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 MUT protein function with a positive predictive value of 95%. This variant disrupts the p.Arg108 amino acid residue in MUT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16281286, 17113806, 22614770, 23430940, 25750861). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192656	SCV001360915	pathogenic	Methylmalonic acidemia	2019-01-14	criteria provided, single submitter	clinical testing	Variant summary: MUT c.322C>T (p.Arg108Cys) results in a non-conservative amino acid change located in the Methylmalonyl-CoA mutase, alpha chain, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 246146 control chromosomes. c.322C>T has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (Worgan_2006, Harrington_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity as measured by decreased incorporation of label from carbon-14 labeled propionate into cellular macromolecules (Worgan_2006). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001376644	SCV001804136	pathogenic	not provided	2021-03-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16281286, 30564975, 24464670, 31622506, 31998365, 31525265, 31466887, 27578510, 29330964, 26454439)
Fulgent Genetics, Fulgent Genetics	RCV000203340	SCV002778542	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2022-02-18	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001192656	SCV004046422	pathogenic	Methylmalonic acidemia		criteria provided, single submitter	clinical testing	This variant has been previously reported as a compound heterozygous and homozygous change in patients with methylmalonic acidemia (PMID: 16281286, 17075691, 24059531, 23045948, 2661559, 22614770, 24464670, 27578510). The c.322C>T (p.Arg108Cys) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.012% (30/251326), and is absent in the homozygous state; thus it is presumed to be rare. The c.322C>T (p.Arg108Cys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.322C>T (p.Arg108Cys) variant is classified as a Pathogenic.
Ambry Genetics	RCV004018538	SCV004969113	pathogenic	not specified	2021-08-18	criteria provided, single submitter	clinical testing	The c.322C>T (p.R108C) alteration is located in exon 2 (coding exon 1) of the MUT gene. This alteration results from a C to T substitution at nucleotide position 322, causing the arginine (R) at amino acid position 108 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.01% (30/251326) total alleles studied. The highest observed frequency was 0.08% (29/34552) of Latino alleles. This mutation has been reported in the homozygous and compound heterozygous state in several individuals with MUT-related methylmalonic aciduria (Worgan, 2006; Zhang, 2019; Han, 2020). Another alteration at the same codon, p.R108H (c.323G>A), has been detected in individuals with MUT-related methylmalonic aciduria in conjunction with a second MUT alteration (Worgan, 2006; Lempp, 2007). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
OMIM	RCV000001964	SCV000022122	pathogenic	METHYLMALONIC ACIDURIA, mut(0) TYPE	2006-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000203340	SCV000258495	not provided	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency		no assertion provided	literature only	mut(0) enzymatic subtype when homozygous
Natera, Inc.	RCV001271723	SCV001453071	pathogenic	Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001376644	SCV001954835	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001376644	SCV001966145	pathogenic	not provided		no assertion criteria provided	clinical testing