rs1553173420

Variant names:

• chr1-1338107-CGGGTGGGGCAGCG-C
• rs1553173420
• NM_001330311.2:c.1571_1583delCGCTGCCCCACCC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001330311.2(DVL1):​c.1571_1583delCGCTGCCCCACCC​(p.Pro524ArgfsTer146) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P524P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DVL1 NM_001330311.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.99
• Publications: 0 publications found

Genes affected

DVL1 (HGNC:3084): (dishevelled segment polarity protein 1) DVL1, the human homolog of the Drosophila dishevelled gene (dsh) encodes a cytoplasmic phosphoprotein that regulates cell proliferation, acting as a transducer molecule for developmental processes, including segmentation and neuroblast specification. DVL1 is a candidate gene for neuroblastomatous transformation. The Schwartz-Jampel syndrome and Charcot-Marie-Tooth disease type 2A have been mapped to the same region as DVL1. The phenotypes of these diseases may be consistent with defects which might be expected from aberrant expression of a DVL gene during development. [provided by RefSeq, Jul 2008]

DVL1 Gene-Disease associations (from GenCC):

• autosomal dominant Robinow syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant Robinow syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-1338107-CGGGTGGGGCAGCG-C is Pathogenic according to our data. Variant chr1-1338107-CGGGTGGGGCAGCG-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 488047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330311.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DVL1	NM_001330311.2	MANE Select	c.1571_1583delCGCTGCCCCACCC	p.Pro524ArgfsTer146	frameshift	Exon 14 of 15	NP_001317240.1	O14640-1
	DVL1	NM_004421.3		c.1496_1508delCGCTGCCCCACCC	p.Pro499ArgfsTer146	frameshift	Exon 14 of 15	NP_004412.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DVL1	ENST00000378888.10	TSL:5 MANE Select	c.1571_1583delCGCTGCCCCACCC	p.Pro524ArgfsTer146	frameshift	Exon 14 of 15	ENSP00000368166.5	O14640-1
	DVL1	ENST00000378891.9	TSL:1	c.1496_1508delCGCTGCCCCACCC	p.Pro499ArgfsTer146	frameshift	Exon 14 of 15	ENSP00000368169.5	O14640-2
	DVL1	ENST00000874577.1		c.1736_1748delCGCTGCCCCACCC	p.Pro579ArgfsTer146	frameshift	Exon 14 of 15	ENSP00000544636.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Autosomal dominant Robinow syndrome 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553173420; hg19: chr1-1273487;