Submissions for variant NM_021930.6(RINT1):c.1333+1G>A

gnomAD frequency: 0.00005  dbSNP: rs375350359

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mayo Clinic Laboratories, Mayo Clinic	RCV000660530	SCV000782632	uncertain significance	not provided	2017-02-09	criteria provided, single submitter	clinical testing
Invitae	RCV000660530	SCV000949740	likely pathogenic	not provided	2023-09-08	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 9 of the RINT1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs375350359, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with breast cancer, colorectal cancer, and/or recurrent acute liver failure (PMID: 25050558, 31204009, 32283892, 33099839). ClinVar contains an entry for this variant (Variation ID: 547947). Studies have shown that disruption of this splice site results in skipping of exon 9 and introduces a premature termination codon and introduces a premature termination codon (PMID: 25050558, 31204009). The resulting mRNA is expected to undergo nonsense-mediated decay. 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.
Ambry Genetics	RCV002386132	SCV002692949	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-10	criteria provided, single submitter	clinical testing	The c.1333+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 9 of the RINT1 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been reported in a cohort of 798 multiple-case breast cancer families, and was show to result in a frameshift and subsequent skipping of exon 9 via a RT-PCR assay performed on cDNA derived from a carrier of 1333+1G>A (Park DJ et al. Cancer Discov, 2014 Jul;4:804-15). This alteration has also been reported in a compound heterozygous state in two individuals with personal history of a multisystem disorder including pediatric acute liver failure and skeletal abnormalities (Cousin MA et al. Am. J. Hum. Genet., 2019 07;105:108-121). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, the gene-disease association for RINT1 is limited. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000660530	SCV004155734	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	RINT1: PVS1, BS1
Working Group: Pediatric metabolic liver diseases, University Hospital Heidelberg	RCV000787311	SCV000864213	pathogenic	Fulminant hepatic failure	2019-01-14	no assertion criteria provided	research
OMIM	RCV000853563	SCV000996529	pathogenic	Infantile liver failure syndrome 3	2019-10-24	no assertion criteria provided	literature only