Submissions for variant NM_006736.6(DNAJB2):c.352+1G>A

gnomAD frequency: 0.00002  dbSNP: rs756614404

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000201941	SCV000936697	pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 5	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 of the DNAJB2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs756614404, gnomAD 0.03%). Disruption of this splice site has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 22522442, 27083531). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217886). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects DNAJB2 function (PMID: 22522442). Studies have shown that disruption of this splice site results in complete or partial retention of intron 5 and introduces a premature termination codon (PMID: 22522442). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo	RCV002051587	SCV001934603	pathogenic	Charcot-Marie-Tooth disease X-linked dominant 1	2021-07-20	criteria provided, single submitter	research	This sequence change falls in intron 5 of the DNAJB2 gene. This mutation causes abnormal splicing of a gene resulting in a quantitative reduction of the protein product (PMID: 22522442). This variant is not present in population databases (GnomAD and ABraOM) in homozygous status. This variant has been reported in the literature in individuals with AR-CMT2 and DSMA5 and is sometimes associated with Parkinson’s disease and cerebellar ataxia (PMID: 22522442; 27083531; DOI: 10.1016/j.parkreldis.2015.10.361). In summary, the c.352+1G>A variant meets our criteria to be classified as pathogenic.
GeneDx	RCV002243881	SCV002513670	pathogenic	not provided	2022-04-22	criteria provided, single submitter	clinical testing	Functional assay performed on patient's cells demonstrated that c.352+1G>A causes inclusion of intron 5, leading to a truncated protein (Blumen et al., 2012); This variant is associated with the following publications: (PMID: 28018906, 27083531, 26752306, 32093037, 22522442, 31589614, Scalia_2021)
Ambry Genetics	RCV002453731	SCV002613820	pathogenic	Inborn genetic diseases	2019-11-01	criteria provided, single submitter	clinical testing	The c.352+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 4 of the DNAJB2 gene. This alteration has been detected in the homozygous form in affected individuals and segregates with disease (Blumen SC et al. Ann. Neurol., 2012 Apr;71:509-19; Frasquet M et al. J. Neurol. Neurosurg. Psychiatry, 2016 11;87:1265-1268; Lupo V et al. J Mol Diagn, 2016 Mar;18:225-34). In addition, RNA studies have demonstrated that this alteration results in abnormal splicing, but normal RNA and protein is also detected in individuals homozygous for this alteration (Blumen SC et al. Ann. Neurol., 2012 Apr;71:509-19). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
PreventionGenetics, part of Exact Sciences	RCV003407713	SCV004113815	pathogenic	DNAJB2-related condition	2023-09-08	criteria provided, single submitter	clinical testing	The DNAJB2 c.352+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in the homozygous state in multiple individuals with distal hereditary motor neuropathy and/or Charcot-Marie-Tooth disease (Blumen et al. 2012. PubMed ID: 22522442; Frasquet et al. 2016. PubMed ID: 27083531; Lupo et al. 2016. PubMed ID: 26752306). This variant is reported in 0.030% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-220146784-G-A). Variants that disrupt the consensus splice donor site in DNAJB2 are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV000201941	SCV000056670	pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 5	2012-04-01	no assertion criteria provided	literature only
Mendelics	RCV000201941	SCV000256882	pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 5	2014-08-08	no assertion criteria provided	clinical testing
Inherited Neuropathy Consortium	RCV000789088	SCV000928437	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only
Inherited Neuropathy Consortium Ii, University Of Miami	RCV003447123	SCV004174610	uncertain significance	Autosomal recessive distal spinal muscular atrophy 2	2019-12-07	no assertion criteria provided	literature only