rs483352778
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000255.4(MMUT):c.323G>A(p.Arg108His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R108C) has been classified as Pathogenic.
Frequency
Consequence
NM_000255.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMUT | NM_000255.4 | c.323G>A | p.Arg108His | missense_variant | 2/13 | ENST00000274813.4 | |
MMUT | XM_005249143.4 | c.323G>A | p.Arg108His | missense_variant | 2/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMUT | ENST00000274813.4 | c.323G>A | p.Arg108His | missense_variant | 2/13 | 1 | NM_000255.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251292Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135820
GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461844Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727226
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152264Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74436
ClinVar
Submissions by phenotype
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 07, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Oct 03, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital | - | PM2_P+PM3_VS+PP3+PP4 - |
not provided Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2023 | 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) - |
not provided, no classification provided | literature only | Medical Genetics Unit, Ain Shams University Pediatrics Hospital | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | 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. - |
Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Methylmalonic acidemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 10, 2017 | 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. - |
METHYLMALONIC ACIDURIA, mut(0) TYPE Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 21, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at