ClinVar Miner

Submissions for variant NM_016277.5(RAB23):c.346A>G (p.Thr116Ala)

gnomAD frequency: 0.00016  dbSNP: rs138803099
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics, Fulgent Genetics RCV002504577 SCV002815148 uncertain significance RAB23-related Carpenter syndrome 2021-11-02 criteria provided, single submitter clinical testing
Invitae RCV002547648 SCV003288018 uncertain significance Carpenter syndrome 2022-03-18 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 116 of the RAB23 protein (p.Thr116Ala). This variant is present in population databases (rs138803099, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with RAB23-related conditions. ClinVar contains an entry for this variant (Variation ID: 1050024). 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 tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV002547647 SCV003685820 uncertain significance Inborn genetic diseases 2022-11-21 criteria provided, single submitter clinical testing The c.346A>G (p.T116A) alteration is located in exon 4 (coding exon 3) of the RAB23 gene. This alteration results from a A to G substitution at nucleotide position 346, causing the threonine (T) at amino acid position 116 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences RCV003416258 SCV004116526 uncertain significance RAB23-related disorder 2023-12-04 criteria provided, single submitter clinical testing The RAB23 c.346A>G variant is predicted to result in the amino acid substitution p.Thr116Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001356824 SCV001552093 uncertain significance not provided no assertion criteria provided clinical testing The RAB23 p.Thr116Ala variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs138803099) and was also found in control databases in 46 of 282702 chromosomes at a frequency of 0.000163 (Genome Aggregation Database Feb 27, 2017) and was observed in the following populations: Other in 3 of 7212 chromosomes (freq: 0.000416), European (non-Finnish) in 30 of 129036 chromosomes (freq: 0.000233), East Asian in 4 of 19954 chromosomes (freq: 0.000201), South Asian in 6 of 30612 chromosomes (freq: 0.000196), Ashkenazi Jewish in 1 of 10366 chromosomes (freq: 0.000096) and Latino in 2 of 35438 chromosomes (freq: 0.000056), while the variant was not observed in the African and European (Finnish) populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Thr116 residue is conserved in mammals but not in more distantly related organisms, however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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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