ClinVar Miner

Submissions for variant NM_022370.4(ROBO3):c.1838C>T (p.Thr613Ile)

gnomAD frequency: 0.00252  dbSNP: rs200202857
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000899962 SCV001044258 likely benign not provided 2019-12-31 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003950544 SCV004761571 likely benign ROBO3-related condition 2022-01-24 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000899962 SCV001550731 uncertain significance not provided no assertion criteria provided clinical testing The ROBO3 p.Thr613Ile variant was not identified in ClinVar, Cosmic, or LOVD 3.0. The variant was identified in dbSNP (ID: rs200202857) and in control databases in 206 of 280618 chromosomes (1 homozygous) at a frequency of 0.000734 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: African in 192 of 24190 chromosomes (freq: 0.007937), Latino in 13 of 35366 chromosomes (freq: 0.000368) and Other in 1 of 7140 chromosomes (freq: 0.00014), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), and South Asian populations. The T613I variant was identified in a family with hypoplastic Amelogenesis Imperfecta however it was not considered to be damaging (Acevedo_2015_PMID:25928877). The p.Thr613 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. In silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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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