ClinVar

Description

A homozygous deletion of exons 3-19 in MERTK (NM_006343.3) was identified by exome sequencing in one individual with retinitis pigmentosa ([GRCh 38] chr2:111940205_112029659x0). These breakpoints have been estimated by exome sequencing only and therefore may not reflect the true breakpoints. Each copy of the variant was inherited from an unaffected heterozygous parent. The patient phenotype is nonspecific, but is consistent with cases described in the literature and/or published databases with overlapping variants. There is partial overlap with the 3’ and additional exons (NMD is expected to occur) of the MERTK gene. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of MERTK is an established disease mechanism in autosomal recessive MERTK-related retinopathy (https://search.clinicalgenome.org/kb/gene-dosage). This exon deletion has also been reported in at least one other individual with retinitis pigmentosa, who was a compound heterozygote that carried a reported variant of uncertain significance in trans, which increases the likelihood that the exon 3-19 deletion variant is pathogenic (Variation ID: 866432; PMID: 29074561). A slightly larger overlapping deletion has been identified in 0.15% (14/9534) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; Structural variant: DEL_2_21010). Although a deletion overlapping the region of this CNV has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive retinitis pigmentosa. The ACMG/ClinGen evidence codes and points used in this curation are as follows: 1: 0 points, 2: 0.90 points, 3: 0 points, 4-5: 0.23 points; Total: 1.13 points; Riggs 2020 (PMID: 31690835).