ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.257C>T (p.Pro86Leu)

gnomAD frequency: 0.00001  dbSNP: rs769348060
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669290 SCV000794029 likely pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-09-06 criteria provided, single submitter clinical testing
Invitae RCV001376596 SCV001237344 pathogenic not provided 2023-11-20 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 86 of the MUT protein (p.Pro86Leu). This variant is present in population databases (rs769348060, gnomAD 0.01%). This missense change has been observed in individual(s) with methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency (PMID: 16281286, 24330302, 27233228). ClinVar contains an entry for this variant (Variation ID: 553773). 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%. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000669290 SCV002810963 likely pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2022-03-09 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003403555 SCV004111145 likely pathogenic MMUT-related condition 2023-03-21 criteria provided, single submitter clinical testing The MMUT c.257C>T variant is predicted to result in the amino acid substitution p.Pro86Leu. This variant has been reported in the compound heterozygous, presumed compound heterozygous, and homozygous states in individuals with methylmalonic acidemia (Worgan et al. 2006. PubMed ID: 16281286; Patient 31, Chu et al. 2016. PubMed ID: 27233228; Nr. 87, Hörster et al. 2020. PubMed ID: 32754920). The c.257C>T variant was also reported in the homozygous state in two unrelated individuals following newborn screening; however, both patients were asymptomatic (Underhill et al. 2013. PubMed ID: 24330302). This variant was also detected in a study of exome sequencing for inborn errors of metabolism in newborns (Supplemental Table 5, Adhikari et al. 2020. PubMed ID: 32778825). Based on in vitro analysis, the c.257C>T (p.Pro86Leu) variant was reported to result in a mild decrease in enzyme activity relative to control, and it was reported to be a thermolabile substitution (Forny et al. 2014. PubMed ID: 25125334). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-49426923-G-A) and is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/553773/). This variant is interpreted as likely pathogenic.

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