Submissions for variant NM_005908.4(MANBA):c.378+1G>A

gnomAD frequency: 0.00002  dbSNP: rs142029636

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000709926	SCV002310413	likely pathogenic	Beta-D-mannosidosis	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the MANBA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MANBA are known to be pathogenic (PMID: 9384606, 12468273). This variant is present in population databases (rs142029636, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with MANBA-related conditions. ClinVar contains an entry for this variant (Variation ID: 585124). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000709926	SCV002571759	likely pathogenic	Beta-D-mannosidosis	2022-08-04	criteria provided, single submitter	clinical testing	Variant summary: MANBA c.378+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 247646 control chromosomes. To our knowledge, no occurrence of c.378+1G>A in individuals affected with Beta-Mannosidosis and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GenomeConnect, ClinGen	RCV000709926	SCV000840275	not provided	Beta-D-mannosidosis		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.