rs1553173368

Variant names:

• chr1-1337992-TCCCGGTGCTGCCGCTG-T
• rs1553173368
• NM_001330311.2:c.1683_1698delCAGCGGCAGCACCGGG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PP5_Moderate

The NM_001330311.2(DVL1):​c.1683_1698delCAGCGGCAGCACCGGG​(p.Ser562ValfsTer107) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DVL1 NM_001330311.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.74
• 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 6 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. There are 8 pathogenic variants in the truncated region.
• PP5: Variant 1-1337992-TCCCGGTGCTGCCGCTG-T is Pathogenic according to our data. Variant chr1-1337992-TCCCGGTGCTGCCGCTG-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 488048.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DVL1	NM_001330311.2	c.1683_1698delCAGCGGCAGCACCGGG	p.Ser562ValfsTer107	frameshift_variant	Exon 14 of 15	ENST00000378888.10	NP_001317240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DVL1	ENST00000378888.10	c.1683_1698delCAGCGGCAGCACCGGG	p.Ser562ValfsTer107	frameshift_variant	Exon 14 of 15	5	NM_001330311.2	ENSP00000368166.5
DVL1	ENST00000378891.9	c.1608_1623delCAGCGGCAGCACCGGG	p.Ser537ValfsTer107	frameshift_variant	Exon 14 of 15	1		ENSP00000368169.5
DVL1	ENST00000631679.1	c.714_729delCAGCGGCAGCACCGGG	p.Ser239ValfsTer7	frameshift_variant	Exon 7 of 8	5		ENSP00000488181.1
DVL1	ENST00000632445.1	c.612_627delCAGCGGCAGCACCGGG	p.Ser205ValfsTer7	frameshift_variant	Exon 4 of 6	5		ENSP00000488888.1

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant Robinow syndrome 2 Pathogenic:1

Jun 01, 2017

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.7
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1553173368; hg19: chr1-1273372;