ClinVar Miner

Submissions for variant NM_005045.4(RELN):c.397G>A (p.Val133Met)

gnomAD frequency: 0.00001  dbSNP: rs200611900
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002547652 SCV003513531 likely benign Norman-Roberts syndrome; Familial temporal lobe epilepsy 7 2024-07-30 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001357009 SCV001552332 uncertain significance not provided no assertion criteria provided clinical testing The RELN p.Val133Met variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs200611900) and in control databases in 6 of 282608 chromosomes at a frequency of 0.000021 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 1 of 10360 chromosomes (freq: 0.000097), East Asian in 1 of 19920 chromosomes (freq: 0.00005), South Asian in 1 of 30606 chromosomes (freq: 0.000033) and European (non-Finnish) in 3 of 129018 chromosomes (freq: 0.000023), while the variant was not observed in the African, Latino, European (Finnish), and Other populations. The p.Val133 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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