ClinVar Miner

Submissions for variant NM_017671.5(FERMT1):c.1718+2T>C

gnomAD frequency: 0.00002  dbSNP: rs760256639
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
3billion RCV001808218 SCV002058818 pathogenic Kindler syndrome 2022-01-03 criteria provided, single submitter clinical testing Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000024, PM2_M). Patient's phenotype is considered compatible with Kindler syndrome (PP4_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Neuberg Centre For Genomic Medicine, NCGM RCV001808218 SCV002073083 uncertain significance Kindler syndrome criteria provided, single submitter clinical testing The splice donor variant c.1718+2T>C in FERMT1 (NM_017671.4) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.1718+2T>C variant is observed in 6/30,596 (0.0196%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant mutates a splice-donor sequence. In silico tools predict a damaging effect. Since the variant is present in the penultimate exon it is classified as Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV002541468 SCV003443270 pathogenic not provided 2022-02-03 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 1333530). 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. Disruption of this splice site has been observed in individual(s) with Kindler syndrome (PMID: 29130490, 29453417). 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 (rs760256639, gnomAD 0.02%). This sequence change affects a donor splice site in intron 13 of the FERMT1 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 FERMT1 are known to be pathogenic (PMID: 14962093, 21936020).

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