rs1553173367

Variant names:

• chr1-1337992-TC-T
• rs1553173367
• NM_001330311.2:c.1698delG

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001330311.2(DVL1):​c.1698delG​(p.Ser567ValfsTer107) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G566G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DVL1 NM_001330311.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -2.04
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.187 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-1337992-TC-T is Pathogenic according to our data. Variant chr1-1337992-TC-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 488046.Status of the report is criteria_provided_single_submitter, 1 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.1698delG	p.Ser567ValfsTer107	frameshift	Exon 14 of 15	NP_001317240.1	O14640-1
	DVL1	NM_004421.3		c.1623delG	p.Ser542ValfsTer107	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.1698delG	p.Ser567ValfsTer107	frameshift	Exon 14 of 15	ENSP00000368166.5	O14640-1
	DVL1	ENST00000378891.9	TSL:1	c.1623delG	p.Ser542ValfsTer107	frameshift	Exon 14 of 15	ENSP00000368169.5	O14640-2
	DVL1	ENST00000874577.1		c.1863delG	p.Ser622ValfsTer107	frameshift	Exon 14 of 15	ENSP00000544636.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal dominant Robinow syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1553173367; hg19: chr1-1273372;