Submissions for variant NM_015506.3(MMACHC):c.626T>A (p.Val209Glu)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002616325	SCV003506742	uncertain significance	Cobalamin C disease	2022-08-02	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 209 of the MMACHC protein (p.Val209Glu). This variant is present in population databases (rs376653350, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with MMACHC-related conditions. 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 MMACHC 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.
Ambry Genetics	RCV002616324	SCV003720242	uncertain significance	Inborn genetic diseases	2021-07-21	criteria provided, single submitter	clinical testing	The c.626T>A (p.V209E) alteration is located in exon 4 (coding exon 4) of the MMACHC gene. This alteration results from a T to A substitution at nucleotide position 626, causing the valine (V) at amino acid position 209 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV002616325	SCV004178215	uncertain significance	Cobalamin C disease	2023-04-11	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV003481399	SCV004227835	uncertain significance	not provided	2023-03-22	criteria provided, single submitter	clinical testing	PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004783016	SCV005394632	uncertain significance	not specified	2024-09-25	criteria provided, single submitter	clinical testing	Variant summary: MMACHC c.626T>A (p.Val209Glu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 249550 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MMACHC causing Methylmalonic Acidemia With Homocystinuria (6.8e-05 vs 0.0032), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.626T>A in individuals affected with Methylmalonic Acidemia With Homocystinuria and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2188165). Based on the evidence outlined above, the variant was classified as uncertain significance.