Submissions for variant NM_001012339.3(DNAJC21):c.983+1G>A

gnomAD frequency: 0.00003  dbSNP: rs368148362

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000784914	SCV000923455	pathogenic	Bone marrow failure syndrome 3	2024-06-09	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818506	SCV002072135	pathogenic	not provided	2018-11-19	criteria provided, single submitter	clinical testing	DNA sequence analysis of the DNAJC21 gene demonstrated a sequence change in the canonical splice donor site of intron 7, c.983+1G>A. This sequence change has been described in EXAC database with a low population frequency of 0.004% (dbSNP rs368148362). This particular sequence change does not appear to have been described in the literature in other patients with DNAJC21-related disorders, however a different pathogenic sequence change affecting the same nucleotide (c.983+1G>T) has been described in a patient with bone marrow failure syndrome in a homozygous state (PMID: 27346687). This pathogenic sequence change is predicted to affect normal splicing of the DNAJC21 gene and result in an abnormal protein which may be degraded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001818506	SCV002256265	likely pathogenic	not provided	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 7 of the DNAJC21 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 DNAJC21 are known to be pathogenic (PMID: 27346687, 28062395). This variant is present in population databases (rs368148362, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with clinical features of DNAJC21-related conditions (PMID: 27346687). ClinVar contains an entry for this variant (Variation ID: 222066). 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.
Mendelics	RCV002247638	SCV002516310	likely pathogenic	Shwachman-Diamond syndrome 1	2022-05-04	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000784914	SCV002768436	likely pathogenic	Bone marrow failure syndrome 3	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available) (intron 7 of 11). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (16 heterozygotes, 0 homozygotes). (P) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (P) 0703 - Comparable variants have moderate previous evidence for pathogenicity. Alternative nucleotide change at the same location has been reported to be pathogenic (ClinVar, PMID: 27346687) (P) 0803 - Low previous evidence of pathogenicity in unrelated individuals as pathogenic (ClinVar, PMID: 29146883), and also once as VUS (ClinVar). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Neuberg Centre For Genomic Medicine, NCGM	RCV000784914	SCV005042902	likely pathogenic	Bone marrow failure syndrome 3		criteria provided, single submitter	clinical testing	The splice donor c.983+1G>A variant in DNAJC21 gene has previously been reported in homozygous state in an individual affected with DNAJC21-related disorders Tummala H, et al., 2016. The .983+1G>A variant has been reported with allele frequency of 0.006% in gnomAD Exomes and is absent in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic / Likely Pathogenic multiple submissions. Loss of function variants in DNAJC21 gene have been previously reported to be disease causing Tummala H, et al., 2016; Dhanraj et al., 2017. Therefore, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005361217	SCV005917715	likely pathogenic	Shwachman-Diamond syndrome 1; Bone marrow failure syndrome 3	2023-02-10	criteria provided, single submitter	research
Bone Marrow Failure laboratory, Queen Mary University London	RCV000235793	SCV000257533	pathogenic	Inherited bone marrow failure syndrome	2015-12-17	no assertion criteria provided	research
Istanbul Faculty of Medicine, Istanbul University	RCV000784914	SCV004015015	pathogenic	Bone marrow failure syndrome 3	2023-02-15	no assertion criteria provided	clinical testing