NM_203486.3(DLL3):c.661C>T (p.Arg221Ter) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Sep 11, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000426077.26

Allele description [Variation Report for NM_203486.3(DLL3):c.661C>T (p.Arg221Ter)]

NM_203486.3(DLL3):c.661C>T (p.Arg221Ter)

Gene:

DLL3:delta like canonical Notch ligand 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.2

Genomic location:

Preferred name:

NM_203486.3(DLL3):c.661C>T (p.Arg221Ter)

HGVS:

NC_000019.10:g.39504079C>T
NG_008256.1:g.10163C>T
NM_016941.4:c.661C>T
NM_203486.3:c.661C>TMANE SELECT
NP_058637.1:p.Arg221Ter
NP_982353.1:p.Arg221Ter
NC_000019.9:g.39994719C>T
NM_016941.3:c.661C>T
NM_203486.3:c.661C>T

Protein change:

R221*

Links:

dbSNP: rs200275281

NCBI 1000 Genomes Browser:

rs200275281

Molecular consequence:

NM_016941.4:c.661C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_203486.3:c.661C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

ATP-binding protein [Sporosarcina ureilytica]
ATP-binding protein [Sporosarcina ureilytica]
gi|1073966954|gnl|PRJNA344509|BI350 0|gb|AOV06673.1|

Protein

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000535147	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Dec 16, 2016)	germline	clinical testing	Citation Link,
SCV001246315	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Dec 1, 2019)	germline	clinical testing	Citation Link,
SCV004631097	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 11, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12746394, 31680349, 28492532
SCV005197717	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 9, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel mutations in DLL3, a somitogenesis gene encoding a ligand for the Notch signalling pathway, cause a consistent pattern of abnormal vertebral segmentation in spondylocostal dysostosis.

Turnpenny PD, Whittock N, Duncan J, Dunwoodie S, Kusumi K, Ellard S.

J Med Genet. 2003 May;40(5):333-9.

PubMed [citation]

PMID:: 12746394
PMCID:: PMC1735475

Trio-whole-exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations.

Guo W, Lai Y, Yan Z, Wang Y, Nie Y, Guan S, Kuo Y, Zhang W, Zhu X, Peng M, Zhi X, Wei Y, Yan L, Qiao J.

Hum Mutat. 2020 Feb;41(2):432-448. doi: 10.1002/humu.23935. Epub 2019 Nov 11.

PubMed [citation]

PMID:: 31680349

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000535147.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The R221X nonsense variant in the DLL3 gene has been reported previously in association with spondylocostal dysostosis (Ottonello et al., 2014). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R221X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Multiple nonsense and other loss of function variants have been reported in the Human Gene Mutation Database in association with spondylocostal dysostosis (Stenson et al., 2014), supporting the functional importance of this protein.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001246315.26

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004631097.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Arg221*) 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 (rs200275281, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with spondylocostal dysostosis (PMID: 31680349). ClinVar contains an entry for this variant (Variation ID: 391971). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005197717.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

ClinVar

Relating variation to medicine