Submissions for variant NM_001122769.3(LCA5):c.1151del (p.Pro384fs)

dbSNP: rs386834252

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001057042	SCV001221511	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro384Glnfs*18) in the LCA5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 314 amino acid(s) of the LCA5 protein. This variant is present in population databases (rs386834252, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with LCA5-related retinal dystrophy (PMID: 17546029, 26352687). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 966). This variant disrupts a region of the LCA5 protein in which other variant(s) (p.Lys586*) have been determined to be pathogenic (PMID: 23946133, 27624628). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001271951	SCV003845080	pathogenic	Leber congenital amaurosis	2023-02-20	criteria provided, single submitter	clinical testing	Variant summary: LCA5 c.1151delC (p.Pro384GlnfsX18) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar and are associated with Leber Congenital Amaurosis in HGMD. The variant allele was found at a frequency of 4e-06 in 250504 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1151delC has been reported in the literature in multiple individuals affected with Leber Congenital Amaurosis/early-onset retinal degeneration and has been shown to segregate with disease (e.g., denHollander_2007, MacKay_2013, Li_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) have cited the variant, and both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000001017	SCV004190592	pathogenic	Leber congenital amaurosis 5	2023-10-24	criteria provided, single submitter	clinical testing
OMIM	RCV000001017	SCV000021167	pathogenic	Leber congenital amaurosis 5	2007-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000001017	SCV000087064	not provided	Leber congenital amaurosis 5		no assertion provided	literature only
Natera, Inc.	RCV001271951	SCV001453525	pathogenic	Leber congenital amaurosis	2020-09-16	no assertion criteria provided	clinical testing