Submissions for variant NM_000255.4(MMUT):c.544dup (p.Met182fs)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281826	SCV002572314	pathogenic	Methylmalonic acidemia	2022-08-25	criteria provided, single submitter	clinical testing	Variant summary: MUT c.544dupA (p.Met182AsnfsX29) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251008 control chromosomes (gnomAD). c.544dupA has been reported in the literature in bi-allelic form in multiple individuals affected with Methylmalonic Acidemia (examples: Fuchshuber_2000 through HGMD, Forny_2016 and Liang_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and reports the variant as a null allele using propionate incorporation assay (Forny_2016). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.