ClinVar Miner

Submissions for variant NM_014249.4(NR2E3):c.1007T>C (p.Leu336Pro)

gnomAD frequency: 0.00001  dbSNP: rs752883545
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508290 SCV000604568 likely pathogenic not provided 2017-05-05 criteria provided, single submitter clinical testing The NR2E3 c.1007T>C;p.Leu336Pro variant has been described in the medical literature in an individual with enhanced S cone syndrome who also carried a pathogenic NR2E3 variant (Wright 2004). The variant is not listed in the ClinVar database, but is listed in the dbSNP variant database (rs752883545) with an allele frequency of 0.000101 percent (1/99026 alleles) in the Exome Aggregation Consortium. The leucine at codon is highly conserved across species, computational algorithms (Align GVGD, PolyPhen2, SIFT) predict this variant is deleterious, and some functional studies have shown this variant has impaired function (von Alpen 2015). Taken together, this variant is considered likely pathogenic. Pathogenic NR2E3 variants are causative for autosomal recessive retinitis pigmentosa or enhanced S cone syndrome or autosomal dominant retinitis pigmentosa (OMIM#604485). References: von Alpen D et al. Differential dimerization of variants linked to enhanced S-cone sensitivity syndrome (ESCS) located in the NR2E3 ligand-binding domain. Hum Mutat. 2015 Jun;36(6):599-610. Wright AF et al. Mutation analysis of NR2E3 and NRL genes in Enhanced S Cone Syndrome. Hum Mutat. 2004 Nov;24(5):439.
Invitae RCV000508290 SCV003442981 uncertain significance not provided 2022-05-10 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 336 of the NR2E3 protein (p.Leu336Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive enhanced S-cone syndrome (PMID: 15459973). ClinVar contains an entry for this variant (Variation ID: 440010). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects NR2E3 function (PMID: 19898638, 25703721, 28300834). 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.
GeneDx RCV000508290 SCV004023547 likely pathogenic not provided 2023-01-30 criteria provided, single submitter clinical testing Published functional studies suggest a damaging effect with impaired transcriptional regulatory activity and reduced DNA binding (Kanda and Swaroop, 2009; Fulton et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25703721, 24069298, 28300834, 19898638, 15459973, 19718767)
Baylor Genetics RCV003470641 SCV004192057 likely pathogenic Enhanced S-cone syndrome 2022-12-03 criteria provided, single submitter clinical testing

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