rs1553173372

Variant names:

• chr1-1337999-G-GCTGCC
• rs1553173372
• NM_001330311.2:c.1687_1691dupGGCAG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001330311.2(DVL1):​c.1687_1691dupGGCAG​(p.Ser564ArgfsTer112) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. 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:2
• Conservation: PhyloP100: 5.71

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 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 0.19 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-1337999-G-GCTGCC is Pathogenic according to our data. Variant chr1-1337999-G-GCTGCC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 488045.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.1687_1691dupGGCAG	p.Ser564ArgfsTer112	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.1687_1691dupGGCAG	p.Ser564ArgfsTer112	frameshift_variant	Exon 14 of 15	5	NM_001330311.2	ENSP00000368166.5
DVL1	ENST00000378891.9	c.1612_1616dupGGCAG	p.Ser539ArgfsTer112	frameshift_variant	Exon 14 of 15	1		ENSP00000368169.5
DVL1	ENST00000631679.1	c.718_722dupGGCAG	p.Ser241ArgfsTer12	frameshift_variant	Exon 7 of 8	5		ENSP00000488181.1
DVL1	ENST00000632445.1	c.616_620dupGGCAG	p.Ser207ArgfsTer12	frameshift_variant	Exon 4 of 6	5		ENSP00000488888.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant Robinow syndrome 2 Pathogenic:2

Apr 26, 2016

Autoinflammatory diseases unit, CHU de Montpellier

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 2017

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553173372; hg19: chr1-1273379;