ClinVar Miner

Submissions for variant NM_006343.3(MERTK):c.1450G>A (p.Gly484Ser)

gnomAD frequency: 0.00001  dbSNP: rs527236084
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000662015 SCV000784347 uncertain significance Retinitis pigmentosa 38 2018-03-05 criteria provided, single submitter clinical testing
3billion RCV000662015 SCV002058279 uncertain significance Retinitis pigmentosa 38 2022-01-03 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MERTK related disorder (PMID:24265693, PS1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.67, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000012, PM2_M). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp RCV002515922 SCV003524731 pathogenic not provided 2022-02-01 criteria provided, single submitter clinical testing This sequence change affects codon 484 of the MERTK mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MERTK protein. This variant also falls at the last nucleotide of exon 9, which is part of the consensus splice site for this exon. This variant is present in population databases (rs527236084, gnomAD 0.01%). This variant has been observed in individual(s) with inherited retinal dystrophy (PMID: 24265693, 25324289, 32036094, 33353011). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 143138). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Department of Ophthalmology and Visual Sciences Kyoto University RCV000132663 SCV000172614 probable-pathogenic Retinitis pigmentosa no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet RCV000132663 SCV000926608 likely pathogenic Retinitis pigmentosa 2018-04-01 no assertion criteria provided research

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