Submissions for variant NM_178857.6(RP1L1):c.326_327insT (p.Lys111fs)

gnomAD frequency: 0.00106  dbSNP: rs771427543

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000762497	SCV000892822	likely pathogenic	not provided	2018-09-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778850	SCV000915245	uncertain significance	Occult macular dystrophy	2017-04-27	criteria provided, single submitter	clinical testing	The RP1L1 c.326_327insT (p.Lys111GlnfsTer27) variant results in a frameshift and is predicted to result in premature termination of the protein. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for occult macular dystrophy.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000762497	SCV001022901	benign	not provided	2024-12-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000762497	SCV003919530	uncertain significance	not provided	2022-10-17	criteria provided, single submitter	clinical testing	Observed with a nonsense variant on the same allele (in cis) in a patient with syndromic retinitis pigmentosa in published literature; this patient was also heterozygous for a nonsense variant in the PCARE gene (previously known as C2orf71), suggestive of possible digenic inheritance (Liu et al., 2017); Observed in heterozygous state in an individual with retinitis pigmentosa in published literature, although the variant was also present in the heterozygous state in the unaffected mother (Avela et al., 2019); Observed in apparent homozygous state in an individual with no reported history of ophthalmologic disorders in published literature (Spedicati et al., 2021); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34426522, 31087526, 33727708, 27029556)
PreventionGenetics, part of Exact Sciences	RCV003396331	SCV004103949	uncertain significance	RP1L1-related disorder	2022-08-29	criteria provided, single submitter	clinical testing	The RP1L1 c.326_327insT variant is predicted to result in a frameshift and premature protein termination (p.Lys111Glnfs*27). This variant was reported in an individual with retinitis pigmentosa that also carried an additional nonsense variant in RP1L1 on the same allele (in cis) as well as a nonsense variant in C2orf71 (Liu et al 2017. PubMed ID: 27029556). This variant was reported as a variant of uncertain significance in the heterozygous state in an individual with retinitis pigmentosa; however, the unaffected mother was also heterozygous for this variant (Avela K et al 2019. PubMed ID: 31087526). The c.326_327insT variant was also reported in the homozygous state in an individual with no ophthalmologic disorder (Spedicati B et al 2021. PubMed ID: 33727708). This variant is reported in 0.89% of alleles in individuals of European (Finnish) descent in gnomAD, including 1 homozygote indicating this variant may be too common to be a primary cause of disease (http://gnomad.broadinstitute.org/variant/8-10480385-G-GA). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.