ClinVar Miner

Submissions for variant NM_002529.4(NTRK1):c.575-19G>A

gnomAD frequency: 0.00005  dbSNP: rs370828525
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001386283 SCV001586460 pathogenic Hereditary insensitivity to pain with anhidrosis 2023-07-11 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 1073315). This sequence change falls in intron 5 of the NTRK1 gene. It does not directly change the encoded amino acid sequence of the NTRK1 protein. This variant is present in population databases (rs370828525, gnomAD 0.008%). This variant has been observed in individual(s) with congenital insensitivity to pain with anhidrosis (PMID: 29770739). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 29770739). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV002280181 SCV002568744 likely pathogenic not provided 2022-08-25 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect, indicating that a novel cryptic splice acceptor results in the addition of 17 nucleotides with a frameshift that creates a premature stop codon (Geng et al., 2018; Shaikh et al., 2018); This variant is associated with the following publications: (PMID: 30002500, 29770739)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001386283 SCV002819926 pathogenic Hereditary insensitivity to pain with anhidrosis 2022-12-31 criteria provided, single submitter clinical testing Variant summary: NTRK1 c.575-19G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 3' acceptor site. At least two independent publications using a mini-gene splicing assay have confirmed the variant affects mRNA splicing, resulting in a product that incorporates a 17-bp intronic sequence that is predicted to result in a frameshift with a premature termination (P194Lfs*9, Geng_2018, Shaikh_2018). The variant allele was found at a frequency of 4.4e-05 in 159664 control chromosomes (gnomAD). c.575-19G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Hereditary Insensitivity To Pain With Anhidrosis (Geng_2018, Shaikh_2018, Zhao_2020). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab RCV001386283 SCV004048669 likely pathogenic Hereditary insensitivity to pain with anhidrosis 2023-04-11 criteria provided, single submitter clinical testing

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