Description
The EYS p.His2599Arg variant was identified in dbSNP (ID: rs74636274), ClinVar (classified as likely benign by Praxis fuer Humangenetik Tuebingen in 2018) and LOVD 3.0 (predicted to be unlikely pathogenic) but was not identified in Cosmic. The variant was identified in control databases in 1028 of 188578 chromosomes (11 homozygous) at a frequency of 0.005451 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 632 of 76436 chromosomes (freq: 0.008268), South Asian in 187 of 22766 chromosomes (freq: 0.008214), Other in 32 of 5496 chromosomes (freq: 0.005822), Latino in 105 of 25536 chromosomes (freq: 0.004112), Ashkenazi Jewish in 16 of 8788 chromosomes (freq: 0.001821), European (Finnish) in 33 of 20318 chromosomes (freq: 0.001624), African in 22 of 16776 chromosomes (freq: 0.001311), and East Asian in 1 of 12462 chromosomes (freq: 0.00008). The p.H2599R variant was identified in 4/186 patients with retinitis pigmentosa (freq=0.011) in one study and in 1/100 patients with retinitis pigmentosa (freq=0.005) in another study (Audo_2010_PMID: 20333770; Neveling_2012_PMID: 22334370). In a cohort of 245 families with retinitis pigmentosa, the p.H2599R variant was suggested not to be pathogenic as it was identified in the unaffected family members of one family but not in the family members affected with retinitis pigmentosa (Littink_2010_PMID: 20537394). The p.His2599 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | unknown | yes | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
