Submissions for variant NM_000255.4(MMUT):c.323G>A (p.Arg108His)

gnomAD frequency: 0.00001  dbSNP: rs483352778

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000502227	SCV000595871	pathogenic	METHYLMALONIC ACIDURIA, mut(0) TYPE	2016-12-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781608	SCV000919780	pathogenic	Methylmalonic acidemia	2017-11-10	criteria provided, single submitter	clinical testing	Variant summary: The MUT c.323G>A (p.Arg108His) variant involves the alteration of a conserved nucleotide located at the SB, substrate binding (beta alpha) 8 barrel domain (Lempp_2007). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 6/246336 control chromosomes at a frequency of 0.0000244, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUT variant (0.0024152). This variant has been reported in multiple affected individuals mostly as compound heterozygotes and the patients' fibroblasts presented with a marked decrease in MCM enzyme activity (Acquaviva_2001 and Lempp_2007). Variants involving codon R108 (p.R108C, p.R108G, and p.R108H) have been reported in multiple patients with Methylmalonic aciduria suggesting it is a mutation hotspot. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae	RCV000162231	SCV000954894	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 108 of the MUT protein (p.Arg108His). This variant is present in population databases (rs483352778, gnomAD 0.007%). This missense change has been observed in individual(s) with methylmalonic aciduria (PMID: 11528502, 16281286, 17113806). ClinVar contains an entry for this variant (Variation ID: 100707). 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: 2661559, 16281286, 17075691, 22614770, 23045948, 24059531, 24464670, 27578510). 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.
Fulgent Genetics, Fulgent Genetics	RCV000664555	SCV002805897	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2021-10-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000162231	SCV003845933	pathogenic	not provided	2023-03-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 17113806, 17075691, 25959030, 26454439, 25750861, 16435223, 27233228, 22661206, 23430940, 31466887, 35361390, 15643616, 21671183, 30098236, 31622506, 33413471, 33453710, 35223700, 11528502, 29731766, 32005694, 31998365, 27167370, 16281286, 26018627, 32754920)
Medical Genetics Unit, Ain Shams University Pediatrics Hospital	RCV000162231	SCV000119930	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000664555	SCV000788539	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2017-10-03	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001271722	SCV001453070	pathogenic	Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency	2020-09-16	no assertion criteria provided	clinical testing
Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	RCV000664555	SCV004800885	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency		no assertion criteria provided	clinical testing	PM2_P+PM3_VS+PP3+PP4