Submissions for variant NM_021930.6(RINT1):c.1021C>G (p.Leu341Val)

dbSNP: rs151055286

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001217921	SCV001389781	uncertain significance	not provided	2019-04-26	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with valine at codon 341 of the RINT1 protein (p.Leu341Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs151055286, ExAC 0.03%). This variant has not been reported in the literature in individuals with RINT1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
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	RCV002274153	SCV002097630	likely pathogenic	Thyroid cancer, nonmedullary, 1	2021-12-28	criteria provided, single submitter	research	We identified a heterozygous missense variant (rs151055286, NM_021930: exon8: c.1021C>G: p.L341V) in exon 8 of the RINT1 gene in a Chinese family (Bh#22PTC) with papillary thyroid cancer (PTC) by whole exome sequencing of peripheral-blood DNA from the patients. The variant was present in the proband (Bh#22PTC_II.3) and two other affected family members (Bh#22PTC_II.2 and Bh#22PTC_III.5). The variant has a 0.002% mutant allele frequency in ExAC. We found that the L341V variant disrupts the interaction of RINT1 with RAD50 by co-immunoprecipitation assays in HEK293T cells. Based on these clinical and genetic evidence, the loss-of-function variant in RINT1 is considered a likely Pathogenic Variant.
Ambry Genetics	RCV004034049	SCV002669080	uncertain significance	not specified	2023-06-20	criteria provided, single submitter	clinical testing	The p.L341V variant (also known as c.1021C>G), located in coding exon 8 of the RINT1 gene, results from a C to G substitution at nucleotide position 1021. The leucine at codon 341 is replaced by valine, an amino acid with highly similar properties. This variant was reported in 6/60,466 breast cancer cases and in 4/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.