Submissions for variant NM_021625.5(TRPV4):c.2336+1G>A

gnomAD frequency: 0.00001  dbSNP: rs771778984

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001172895	SCV001335970	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Invitae	RCV001873602	SCV002179243	uncertain significance	Charcot-Marie-Tooth disease axonal type 2C	2023-12-02	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 14 of the TRPV4 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), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TRPV4 cause disease. This variant is present in population databases (rs771778984, gnomAD 0.002%). Disruption of this splice site has been observed in individual(s) with clinical features of TRPV4-related conditions (PMID: 32376792; Invitae). ClinVar contains an entry for this variant (Variation ID: 916860). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271624	SCV002556081	uncertain significance	not specified	2022-06-22	criteria provided, single submitter	clinical testing	Variant summary: TRPV4 c.2336+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: Four predict the variant abolishes a 5 prime 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 250270 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2336+1G>A has been reported in the literature in one individual with suspected Charcot-Marie-Tooth disease. This report does not provide unequivocal conclusions about association of the variant with Spondylometaphyseal Dysplasia, Kozlowski Type. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.