NM_203486.3(DLL3):c.712C>T (p.Arg238Ter) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 19, 2024
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:: RCV001558657.8

Allele description [Variation Report for NM_203486.3(DLL3):c.712C>T (p.Arg238Ter)]

NM_203486.3(DLL3):c.712C>T (p.Arg238Ter)

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.712C>T (p.Arg238Ter)

HGVS:

NC_000019.10:g.39504130C>T
NG_008256.1:g.10214C>T
NM_016941.4:c.712C>T
NM_203486.3:c.712C>TMANE SELECT
NP_058637.1:p.Arg238Ter
NP_982353.1:p.Arg238Ter
NC_000019.9:g.39994770C>T
NM_016941.3:c.712C>T

Protein change:

R238*; ARG238TER

Links:

OMIM: 602768.0006; dbSNP: rs104894675

NCBI 1000 Genomes Browser:

rs104894675

Molecular consequence:

NM_016941.4:c.712C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_203486.3:c.712C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001780652	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Sep 7, 2021)	germline	clinical testing	Citation Link,
SCV002146403	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 19, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12746394, 12791036, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001780652

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Sep 7, 2021)

germline

clinical testing

Citation Link,

SCV002146403

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 19, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

A cluster of autosomal recessive spondylocostal dysostosis caused by three newly identified DLL3 mutations segregating in a small village.

Bonafé L, Giunta C, Gassner M, Steinmann B, Superti-Furga A.

Clin Genet. 2003 Jul;64(1):28-35.

PubMed [citation]

PMID:: 12791036

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV001780652.3

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

Description

Nonsense 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; Observed with a second DLL3 variant in an individual with spondylocostal dysostosis in the published literature (Bonafe et al., 2003); This variant is associated with the following publications: (PMID: 12791036, 23496422, 17213840, 25525159)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002146403.3

#	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.Arg238*) 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 (rs104894675, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with spondylocostal dysostosis (PMID: 12791036). ClinVar contains an entry for this variant (Variation ID: 6833). 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

Last Updated: Sep 29, 2024

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