Submissions for variant NM_000255.4(MMUT):c.2026G>A (p.Ala676Thr)

gnomAD frequency: 0.00011  dbSNP: rs147715336

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001376641	SCV000825137	pathogenic	not provided	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 676 of the MUT protein (p.Ala676Thr). This variant is present in population databases (rs147715336, gnomAD 0.02%). This missense change has been observed in individual(s) with methylmalonic acidemia (internal data). 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: 574601). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
CeGaT Center for Human Genetics Tuebingen	RCV001376641	SCV001747461	pathogenic	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000696572	SCV001752599	likely pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2021-06-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000696572	SCV002517624	pathogenic	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230575	SCV003928880	likely pathogenic	Methylmalonic acidemia	2024-10-14	criteria provided, single submitter	clinical testing	Variant summary: MMUT c.2026G>A (p.Ala676Thr) results in a non-conservative amino acid change located in the Cobalamin (vitamin B12)-binding domain (IPR006158) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 282576 control chromosomes. c.2026G>A has been reported in the literature in individuals affected with Methylmalonic Acidemia (Brasil_2018, Held_2022, Internal Data). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30041674, 35225935). ClinVar contains an entry for this variant (Variation ID: 574601). Based on the evidence outlined above, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003403616	SCV004119052	likely pathogenic	MMUT-related disorder	2023-12-02	no assertion criteria provided	clinical testing	The MMUT c.2026G>A variant is predicted to result in the amino acid substitution p.Ala676Thr. This variant has been reported in the homozygous and compound heterozygous state in two unrelated individuals with cobalamin deficiency (Brasil et al. 2018. PubMed ID: 30041674). This variant was also described, along with a protein-truncating variant, in an individual who tested positive on newborn screening (Held et al. 2022. PubMed ID: 35225935). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. This variant is interpreted as likely pathogenic.