Submissions for variant NM_015506.3(MMACHC):c.434T>C (p.Ile145Thr)

gnomAD frequency: 0.00001  dbSNP: rs759921519

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001961242	SCV002253378	uncertain significance	Cobalamin C disease	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 145 of the MMACHC protein (p.Ile145Thr). This variant is present in population databases (rs759921519, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MMACHC-related conditions. ClinVar contains an entry for this variant (Variation ID: 1463938). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271710	SCV002556216	uncertain significance	not specified	2022-06-28	criteria provided, single submitter	clinical testing	Variant summary: MMACHC c.434T>C (p.Ile145Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 248704 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.434T>C in individuals affected with Methylmalonic Acidemia With Homocystinuria and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV001961242	SCV002792745	uncertain significance	Cobalamin C disease	2021-10-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001961242	SCV004178175	uncertain significance	Cobalamin C disease	2023-04-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004044507	SCV005006996	uncertain significance	Inborn genetic diseases	2023-10-10	criteria provided, single submitter	clinical testing	The c.434T>C (p.I145T) alteration is located in exon 4 (coding exon 4) of the MMACHC gene. This alteration results from a T to C substitution at nucleotide position 434, causing the isoleucine (I) at amino acid position 145 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.