Submissions for variant NM_203486.3(DLL3):c.599_603dup (p.Pro202fs)

dbSNP: rs786200899

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007230	SCV000917279	pathogenic	Spondylocostal dysostosis 1, autosomal recessive	2018-10-16	criteria provided, single submitter	clinical testing	Variant summary: DLL3 c.599_603dupGCGGT (p.Pro202AlafsX41) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 7.1e-05 in 113278 control chromosomes (gnomAD and publications).The variant, c.599_603dupGCGGT, has been reported in the literature in one consanguineous family in multiple homozygotes affected with Spondylocostal dysostosis 1 and in one heterozygote with a milder phenotype (Bulman_2000). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics	RCV000990213	SCV001141083	pathogenic	Leukodystrophy and acquired microcephaly with or without dystonia;	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001531895	SCV001747217	pathogenic	not provided	2021-05-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001531895	SCV001794534	pathogenic	not provided	2023-02-03	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 10742114, 29620724, 31589614, 35137400, 14708096, 12746394)
Revvity Omics, Revvity	RCV000007230	SCV002020385	pathogenic	Spondylocostal dysostosis 1, autosomal recessive	2020-03-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001531895	SCV002230086	pathogenic	not provided	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro202Alafs*41) in the DLL3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DLL3 are known to be pathogenic (PMID: 12746394). This variant is present in population databases (rs750107624, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with spondylocostal dysostosis (PMID: 10742114, 29620724). ClinVar contains an entry for this variant (Variation ID: 6828). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000007230	SCV004040988	pathogenic	Spondylocostal dysostosis 1, autosomal recessive	2023-07-04	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000007230	SCV005061106	pathogenic	Spondylocostal dysostosis 1, autosomal recessive		criteria provided, single submitter	clinical testing	The observed frameshift c.599_603dup(p.Pro202AlafsTer41) variant in DLL3 gene has been reported previously in homozygous state in individual(s) affected with spondylocostal dysostosis 1 (Maddirevula S, et al., 2018; Bulman MP, et al., 2000). The p.Pro202AlafsTer41 variant has been reported with allele frequency of 0.006% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Proline 202, changes this amino acid to Alanine residue, and creates a premature Stop codon at position 41 of the new reading frame, denoted p.Pro202AlafsTer41. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in DLL3 gene have been previously reported to be pathogenic (Turnpenny PD, et al., 2003). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000007230	SCV005648752	pathogenic	Spondylocostal dysostosis 1, autosomal recessive	2024-04-23	criteria provided, single submitter	clinical testing
OMIM	RCV000007230	SCV000027426	pathogenic	Spondylocostal dysostosis 1, autosomal recessive	2000-04-01	no assertion criteria provided	literature only