Submissions for variant NM_014254.3(RXYLT1):c.325+1G>T

gnomAD frequency: 0.00001  dbSNP: rs1592838547

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001237057	SCV001409805	likely pathogenic	not provided	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 of the RXYLT1 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 RXYLT1 are known to be pathogenic (PMID: 23217329, 23519211, 31742715). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RXYLT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 963083). 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	RCV003486973	SCV004241346	likely pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 10	2023-12-19	criteria provided, single submitter	clinical testing	Variant summary: RXYLT1 c.325+1G>T 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: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.325+1G>T in individuals affected with Muscular Dystrophy-Dystroglycanopathy (congenital With Brain And Eye Anomalies), Type A, 10 and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.