ClinVar Miner

Submissions for variant NM_001199107.2(TBC1D24):c.845C>G (p.Pro282Arg) (rs747538224)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254691 SCV000243339 pathogenic not provided 2018-10-25 criteria provided, single submitter clinical testing The P282R missense variant in the TBC1D24 gene has been reported previously in individuals with focal seizures and MMPSI who also harbored a second TBC1D24 variant (Appavu et al., 2016; Balestrini et al., 2016). The P282R variant has been observed in the apparently homozygous or compound heterozygous state in several individuals referred for epilepsy panel testing at GeneDx. The P282R variant is observed in 44/34420 (0.13%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). The P282R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, P282R is considered a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000189692 SCV000249121 uncertain significance not specified 2014-08-08 criteria provided, single submitter clinical testing
Invitae RCV000469036 SCV000549904 pathogenic Epileptic encephalopathy, early infantile, 1; Deafness, autosomal dominant 65; Caused by mutation in the TBC1 domain family, member 24 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 282 of the TBC1D24 protein (p.Pro282Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is present in population databases (rs747538224, ExAC 0.2%). This variant has been observed to segregate with autosomal recessive intractable epilepsy and developmental delays in a family (PMID: 27502353, Invitae). It has also be reported on the opposite chromosome (in trans) from a pathogenic TBC1D24 variant in an individual affected with developmental and epileptic encephalopathy (PMID: 29100083) and has been observed in the homozygous state in several individuals affected with intractable epilepsy and developmental delays (Invitae). ClinVar contains an entry for this variant (Variation ID: 207505). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000623272 SCV000741949 likely pathogenic Inborn genetic diseases 2017-09-13 criteria provided, single submitter clinical testing
Baylor Genetics RCV001330478 SCV001522162 pathogenic DOORS syndrome 2019-10-22 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678853 SCV000805044 uncertain significance developmental delay with seizures 2016-08-15 no assertion criteria provided clinical testing
Clinical Genomics Program, Stanford Medicine RCV000254691 SCV001427226 pathogenic not provided 2020-03-02 no assertion criteria provided clinical testing The p.Pro282Arg variant in the TBC1D24 gene has been previously reported in at least 17 unrelated individuals with seizures and developmental delay, and co-segregated with disease in at least 3 affected relatives from 3 families (Appavu et al., 2016; GeneDx, personal communication, March 2, 2020; Hamdan et al., 2017; Invitae, personal communication, February 12, 2020). All affected individuals were homozygous or compound heterozygous. This variant was determined to be in trans with at least 4 different likely pathogenic or pathogenic variants consistent with autosomal recessive inheritance (GeneDx, personal communication, March 2, 2020; Hamdan et al., 2017; Invitae, personal communication, February 12, 2020). The presence of this variant with a diseaseassociated variant on the opposite allele increases suspicion for its pathogenicity. The p.Pro282Arg variant has also been identified in 45/35,374 Latino chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Pro282Arg variant as pathogenic for autosomal recessive TBC1D24-associated disorders based on the information above. [ACMG evidence codes used: PM2; PM3_verystrong; PP1_moderate; PP3]

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