Submissions for variant NM_015506.3(MMACHC):c.434dup (p.Ser146fs)

gnomAD frequency: 0.00001  dbSNP: rs768978351

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001932334	SCV002124027	pathogenic	Cobalamin C disease	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser146Ilefs*36) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 137 amino acid(s) of the MMACHC protein. This variant is present in population databases (rs768978351, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with methylmalonic aciduria and homocystinuria (PMID: 19370762, 30209273). ClinVar contains an entry for this variant (Variation ID: 1362501). This variant disrupts a region of the MMACHC protein in which other variant(s) (p.Tyr222*) have been determined to be pathogenic (PMID: 16311595, 19767224, 30157807). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001932334	SCV002797568	likely pathogenic	Cobalamin C disease	2022-03-30	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001932334	SCV004178170	likely pathogenic	Cobalamin C disease	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001932334	SCV004193182	pathogenic	Cobalamin C disease	2023-12-06	criteria provided, single submitter	clinical testing