Submissions for variant NM_004525.3(LRP2):c.3667+1G>A

gnomAD frequency: 0.00001  dbSNP: rs752197557

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Daryl Scott Lab, Baylor College of Medicine	RCV001269295	SCV001448641	likely pathogenic	Donnai-Barrow syndrome	2020-11-11	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001269295	SCV002809863	likely pathogenic	Donnai-Barrow syndrome	2021-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002541641	SCV003229302	likely pathogenic	not provided	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 24 of the LRP2 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 LRP2 are known to be pathogenic (PMID: 17632512, 25682901). This variant is present in population databases (rs752197557, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with clinical features of Donnai-Barrow syndrome (PMID: 33461977). ClinVar contains an entry for this variant (Variation ID: 987893). 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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001269295	SCV004807519	pathogenic	Donnai-Barrow syndrome	2024-03-29	criteria provided, single submitter	clinical testing