Submissions for variant NM_000303.3(PMM2):c.566_571delinsGTGGATTTCC (p.Lys189fs)

dbSNP: rs2060686245

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264564	SCV001442782	likely pathogenic	PMM2-congenital disorder of glycosylation	2020-10-05	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.566_571delins10 (c.566_571delinsGTGGATTTCC, p.Lys189SerfsX12) 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 was absent in 282876 control chromosomes. c.566_571delins10 has been reported in the literature in at least one individual affected with Congenital Disorder Of Glycosylation Type 1a (Tayebi_2002). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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 likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001264564	SCV002793548	likely pathogenic	PMM2-congenital disorder of glycosylation	2021-12-30	criteria provided, single submitter	clinical testing
GeneDx	RCV003227020	SCV003923406	likely pathogenic	not provided	2023-05-05	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 58 amino acids are replaced with 11 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11891694)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001264564	SCV004536680	pathogenic	PMM2-congenital disorder of glycosylation	2023-09-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys189Serfs*12) in the PMM2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 58 amino acid(s) of the PMM2 protein. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with congenital disorders of glycosylation (PMID: 11891694). This variant is also known as c.565-571delAGAGAT insGTGGATTTCC. This variant disrupts a region of the PMM2 protein in which other variant(s) (p.Leu243Pro) have been determined to be pathogenic (Invitae). 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.