ClinVar Miner

Submissions for variant NM_002529.4(NTRK1):c.1354+1G>T

gnomAD frequency: 0.00003  dbSNP: rs764771898
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001212380 SCV001383963 pathogenic Hereditary insensitivity to pain with anhidrosis 2023-06-05 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 942399). This variant is also known as c.1354+1G>T. Disruption of this splice site has been observed in individual(s) with congenital insensitivity to pain with anhidrosis (PMID: 32219930, 33422294). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs764771898, gnomAD 0.03%). This sequence change affects a donor splice site in intron 10 of the NTRK1 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 NTRK1 are known to be pathogenic (PMID: 10982191).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001212380 SCV003929097 likely pathogenic Hereditary insensitivity to pain with anhidrosis 2023-04-26 criteria provided, single submitter clinical testing Variant summary: NTRK1 c.1336+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 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251370 control chromosomes. c.1336+1G>T has been reported in the literature in individuals affected with Hereditary Insensitivity To Pain With Anhidrosis (Zhao_2020, Li_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33422294, 32219930). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genome-Nilou Lab RCV001212380 SCV004048719 likely pathogenic Hereditary insensitivity to pain with anhidrosis 2023-04-11 criteria provided, single submitter clinical testing

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