ClinVar Miner

Submissions for variant NM_001122769.3(LCA5):c.2T>C (p.Met1Thr)

gnomAD frequency: 0.00001  dbSNP: rs1331645027
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001306759 SCV001496141 pathogenic not provided 2023-12-17 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the LCA5 mRNA. The next in-frame methionine is located at codon 336. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with LCA5-related conditions (PMID: 23946133; Invitae). ClinVar contains an entry for this variant (Variation ID: 1009292). This variant disrupts a region of the LCA5 protein in which other variant(s) (p.Ala212Pro) have been observed in individuals with LCA5-related conditions (PMID: 27067258). 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 RCV001586119 SCV001821314 uncertain significance not specified 2021-08-19 criteria provided, single submitter clinical testing Variant summary: LCA5 c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251410 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2T>C in individuals affected with Leber Congenital Amaurosis and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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