Submissions for variant NM_178857.6(RP1L1):c.5821C>T (p.Gln1941Ter)

dbSNP: rs201017122

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000376023	SCV000471074	likely benign	Occult macular dystrophy	2016-06-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000584938	SCV000693258	uncertain significance	not provided	2017-07-01	criteria provided, single submitter	clinical testing
DBGen Ocular Genomics	RCV001591030	SCV001815965	likely pathogenic	Retinitis pigmentosa 88	2021-06-22	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV001591030	SCV002498690	uncertain significance	Retinitis pigmentosa 88	2022-04-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature termination codon at position 1941 in exon 4 (of 4) of RP1L1, p.(Gln1941*). While this is not anticipated to result in nonsense mediated decay, it is expected to remove the last 460 amino acids in a region of unknown function. At least one pathogenic downstream predicted loss of function variant has been reported to cause retinitis pigmentosa (PMID: 26355662, 32360662 ). The variant is present in a large population cohort at a frequency of 0.04% (rs201017122, 110/280,716 alleles, 0 homozygotes in gnomAD v2.1), with an allele frequency of 0.08% in the Latino/admixed American population. It has been identified in a case with an inherited retinal disorder with a variant of uncertain significance on the second allele, and segregates with disease in a single family (PMID: 33302505). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PVS1_Strong, PP1.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230487	SCV003928733	uncertain significance	not specified	2023-04-27	criteria provided, single submitter	clinical testing	Variant summary: RP1L1 c.5821C>T (p.Gln1941X) results in a premature termination codon located in the last exon, and is therefore not expected to result in nonsense mediated decay. No variants have been reliably classified as pathogenic in ClinVar. The variant allele was found at a frequency of 0.00038 in 249526 (96/249526) control chromosomes. c.5821C>T has been reported in the literature in individuals affected with blindnes or inherited retinal dystrophies, without strong evidence for causality (Dineiro_2020, Martin-Sanchez_2020, Rodriguez-Munoz_2020). In one report, the variant was said to segregate in at least 1 additional family member, however the second variant in this cases was of unknown significance (Martin-Sanchez_2020). These reports do not provide unequivocal conclusions about association of the variant with RP1L1-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32483926, 33302505, 32036094). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: two submitters classified the variant as VUS while one classified as likely benign and likely pathogenic, respectively. Based on the evidence outlined above, the variant was classified as uncertain significance.