NM_203486.3(DLL3):c.677C>G (p.Pro226Arg) AND Spondylocostal dysostosis 1, autosomal recessive

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Aug 24, 2020
Review status:: criteria provided, conflicting classifications

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:: RCV001134171.14

Allele description [Variation Report for NM_203486.3(DLL3):c.677C>G (p.Pro226Arg)]

NM_203486.3(DLL3):c.677C>G (p.Pro226Arg)

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.677C>G (p.Pro226Arg)

HGVS:

NC_000019.10:g.39504095C>G
NG_008256.1:g.10179C>G
NM_016941.4:c.677C>G
NM_203486.3:c.677C>GMANE SELECT
NP_058637.1:p.Pro226Arg
NP_982353.1:p.Pro226Arg
NC_000019.9:g.39994735C>G
NM_016941.3:c.677C>G

Protein change:

P226R

Links:

dbSNP: rs145191532

NCBI 1000 Genomes Browser:

rs145191532

Molecular consequence:

NM_016941.4:c.677C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_203486.3:c.677C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Spondylocostal dysostosis 1, autosomal recessive (SCDO1)
Identifiers:: MONDO: MONDO:0020692; MedGen: CN032975; Orphanet: 2311; OMIM: 277300

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001293900	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Likely benign (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV001471617	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Aug 24, 2020)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001293900

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Likely benign
(Jan 13, 2018)

germline

clinical testing

Citation Link,

SCV001471617

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Uncertain significance
(Aug 24, 2020)

germline

clinical testing

Citation Link

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

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001293900.1

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001471617.1

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

Description

The DLL3 c.677C>G; p.Pro226Arg variant (rs145191532), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 286841). This variant is found in the South Asian population with an allele frequency of 0.40% (121/30616 alleles) in the Genome Aggregation Database. The proline at codon 226 is moderately conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. While the relatively high population frequency suggests that this may be a benign variant, given the lack of clinical and functional data, the significance of the p.Pro226Arg variant is uncertain at this time.

#	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: Jul 19, 2025

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