ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.14519T>C (p.Leu4840Pro) (rs143275144)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766738 SCV000617260 uncertain significance not provided 2017-10-31 criteria provided, single submitter clinical testing The L4840P variant in the USH2A gene has been published as a homozygous variant apparently on the same allele (in cis) with another variant, C1900G (Bonnet et al., 2016). The L4840P variant has also been published as a heterozygous variant in a patient diagnosed with non-syndrome retinitis pigmentosa and was classified as a variant of uncertain significance (McGee et al., 2010). The L4840P variant is observed in 52/126,532 (0.042%) alleles from individuals of European background, in large population cohorts and in 1 unaffected homozygote undergoing testing at GeneDx (Lek et al., 2016). The L4840P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Leucine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret L4840P as a variant of uncertain significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041765 SCV000065461 uncertain significance not specified 2016-12-08 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Leu4840Pro va riant in USH2A has been previously reported by our laboratory in 1 individual wi th hearing loss who carried a homozygous pathogenic variant in another gene that explained the hearing loss. This variant has also been reported in 3 individual s with either retinitis pigmentosa or Usher syndrome. It was homozygous in 1 ind ividual, but a variant affecting the remaining copy of USH2A was not identified in the other 2 individuals (McGee 2010, Baux 2014, Bonnet 2016). This variant ha s been identified in 28/66738 European chromosomes by the Exome Aggregation Cons ortium (ExAC, http://exac.broadinstitute.org; dbSNP rs143275144); however, its f requency is not high enough to rule out a pathogenic role. The leucine (Leu) at position 4840 is not highly conserved in mammals and evolutionary distant specie s, and two mammals (prairie vole and Golden hamster) have a proline (Pro) at the position, supporting that this change at this position may be tolerated. In su mmary, while the clinical significance of the p.Leu4804Pro variant is uncertain, these data suggest that it is more likely to be benign.

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