Submissions for variant NM_001142800.2(EYS):c.881C>G (p.Ser294Ter)

gnomAD frequency: 0.00007  dbSNP: rs752683070

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000190584	SCV000245608	pathogenic	Retinitis pigmentosa 25	2014-12-15	criteria provided, single submitter	clinical testing	The p.Ser294X variant in EYS has not been previously reported in individuals with retinitis pigmentosa but has been identified in 0.038% (4/10520) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 294, which is predicted to lead to a truncated or absent protein. Complete loss of EYS function is an established disease mechanism in individuals with autosomal recessive retinitis pigmentosa. In summary, this variant meets our criteria to be classified as pathogenic for retinitis pigmentosa in an autosomal recessive manner.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001069674	SCV001234860	pathogenic	not provided	2024-10-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser294*) in the EYS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EYS are known to be pathogenic (PMID: 18836446, 20333770). This variant is present in population databases (rs752683070, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with EYS-related conditions. ClinVar contains an entry for this variant (Variation ID: 208579). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074844	SCV001240445	likely pathogenic	Retinal dystrophy	2019-07-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230445	SCV003929177	likely pathogenic	Retinitis pigmentosa	2023-04-04	criteria provided, single submitter	clinical testing	Variant summary: EYS c.881C>G (p.Ser294X) 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 by our laboratory. The variant allele was found at a frequency of 2.4e-05 in 250524 control chromosomes (gnomAD). To our knowledge, no occurrence of c.881C>G in individuals affected with Retinitis Pigmentosa and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic (n=1) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000190584	SCV004192887	likely pathogenic	Retinitis pigmentosa 25	2024-03-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001069674	SCV005401474	likely pathogenic	not provided	2024-05-14	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Has not been previously published as pathogenic or benign in association with EYS-related retinitis pigmentosa to our knowledge; This variant is associated with the following publications: (PMID: 31964843)