Submissions for variant NM_021930.6(RINT1):c.1107+1G>T

gnomAD frequency: 0.00001  dbSNP: rs200989342

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000809712	SCV000949882	likely pathogenic	not provided	2023-01-13	criteria provided, single submitter	clinical testing	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. 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: 653869). This variant has not been reported in the literature in individuals affected with RINT1-related conditions. This variant is present in population databases (rs200989342, gnomAD 0.03%). This sequence change affects a donor splice site in intron 8 of the RINT1 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 RINT1 are known to be pathogenic (PMID: 31204009).
Dept. of Medical Genetics, The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission	RCV002273829	SCV002097629	likely pathogenic	Thyroid cancer, nonmedullary, 1	2021-12-28	criteria provided, single submitter	research	We identified a heterozygous donor splice site variant (rs200989342, NM_021930: exon8: c.1107+1G>T) in intron 8 of the RINT1 gene in two unrelated Chinese patients with papillary thyroid cancer (PTC) by whole exome sequencing of DNA in peripheral-blood cells from the patients. The same sequence change at somatic level was also found in a formalin-fixed paraffin-embedded (FFPE) tumor specimen from the third Chinese individual with PTC. The variant has a 0.003% mutant allele frequency in ExAC. We used RT-PCR and Sanger sequencing to determine that the variant causes RINT1 exon 8 skipping and results in a marked decrease in mutant mRNA in the normal thyroid tissue from one variant carrier and in the FFPE tumor specimen from another variant carrier. Based on these clinical and genetic evidence, the loss-of-function variant in RINT1 is considered a likely Pathogenic Variant.