Submissions for variant NM_006736.6(DNAJB2):c.230-2A>G

gnomAD frequency: 0.00012  dbSNP: rs369661561

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000214459	SCV000279678	uncertain significance	not provided	2022-03-11	criteria provided, single submitter	clinical testing	Identified in an individual from a cohort with suspected Charcot-Marie-Tooth disease, however, it is unclear if this individual harbored a second DNAJB2 variant and clinical information was not provided (Volodarsky et al., 2021); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25274842, 22522442, 32376792)
Invitae	RCV000545700	SCV000652822	likely pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 5	2023-11-18	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 4 of the DNAJB2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DNAJB2 are known to be pathogenic (PMID: 22522442, 25274842). This variant is present in population databases (rs369661561, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 234675). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000214459	SCV000892627	likely pathogenic	not provided	2018-08-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000214459	SCV001713261	likely pathogenic	not provided	2020-03-17	criteria provided, single submitter	clinical testing	PVS1, PM2
Ambry Genetics	RCV002444871	SCV002734107	uncertain significance	Inborn genetic diseases	2020-12-10	criteria provided, single submitter	clinical testing	The c.230-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 4 in the DNAJB2 gene. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. The exact functional effect of the missing amino acids is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GenomeConnect - Invitae Patient Insights Network	RCV001535597	SCV001749606	not provided	Charcot-Marie-Tooth disease type 2; Neuronopathy, distal hereditary motor, autosomal recessive 5		no assertion provided	phenotyping only	Variant interpreted as Likely pathogenic and reported on 11-23-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.