Submissions for variant NM_172250.3(MMAA):c.304G>A (p.Ala102Thr)

gnomAD frequency: 0.00001  dbSNP: rs1328584680

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000627007	SCV000747710	uncertain significance	Cataract; Microcephaly; Severe global developmental delay	2017-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV000642157	SCV000763811	uncertain significance	Methylmalonic aciduria, cblA type	2022-06-30	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 102 of the MMAA protein (p.Ala102Thr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with a positive newborn screening result for MMAA-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 523564). 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 MMAA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV000998299	SCV001154287	likely pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	MMAA: PM2, PM3, PP4:Moderate
GeneDx	RCV000998299	SCV001987884	uncertain significance	not provided	2019-08-29	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Natera, Inc.	RCV000642157	SCV002084821	uncertain significance	Methylmalonic aciduria, cblA type	2020-02-12	no assertion criteria provided	clinical testing
Clinical Genetics, Synlab MVZ Humangenetik Freiburg	RCV000642157	SCV003934912	likely pathogenic	Methylmalonic aciduria, cblA type	2022-10-12	no assertion criteria provided	clinical testing	This variant was found in an affected patient in trans to a known pathogenic truncating variant. The variant is present in the gnomAD database at extreme low frequency (2x het., gnomAd v.3.1.2) and affects a highly conserved residue.