Submissions for variant NM_015506.3(MMACHC):c.688C>T (p.Arg230Ter)

gnomAD frequency: 0.00006  dbSNP: rs201183360

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000579162	SCV000680549	likely pathogenic	not provided	2022-09-07	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 52 amino acids are lost; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31589614, 22642810, 26990548)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000984195	SCV002570885	likely pathogenic	Cobalamin C disease	2022-07-30	criteria provided, single submitter	clinical testing	Variant summary: MMACHC c.688C>T (p.Arg230X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.8e-05 in 249066 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.688C>T in individuals affected with Methylmalonic Acidemia With Homocystinuria and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000984195	SCV003298340	uncertain significance	Cobalamin C disease	2022-05-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg230*) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the MMACHC protein. This variant is present in population databases (rs201183360, 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: 488706). This variant disrupts a region of the MMACHC protein in which other variant(s) (p.Arg267) have been observed in individuals with MMACHC-related conditions (PMID: 24126030). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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.
Baylor Genetics	RCV000984195	SCV004193175	likely pathogenic	Cobalamin C disease	2023-10-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000984195	SCV001132250	likely pathogenic	Cobalamin C disease	2017-01-25	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001275220	SCV001460144	likely pathogenic	Methylmalonic acidemia with homocystinuria cblC	2020-09-16	no assertion criteria provided	clinical testing