rs1553173420

Positions:

• chr1-1338107-CGGGTGGGGCAGCG-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001330311.2(DVL1):​c.1571_1583del​(p.Pro524ArgfsTer146) variant causes a frameshift change involving the alteration of a 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. P524P) has been classified as Likely benign.

• 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

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 Pathogenic. Variant got 14 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 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-1338107-CGGGTGGGGCAGCG-C is Pathogenic according to our data. Variant chr1-1338107-CGGGTGGGGCAGCG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 488047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1338107-CGGGTGGGGCAGCG-C is described in Lovd as [Likely_pathogenic]. Variant chr1-1338107-CGGGTGGGGCAGCG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DVL1	NM_001330311.2	c.1571_1583del	p.Pro524ArgfsTer146	frameshift_variant	14/15	ENST00000378888.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DVL1	ENST00000378888.10	c.1571_1583del	p.Pro524ArgfsTer146	frameshift_variant	14/15	5	NM_001330311.2	P3
DVL1	ENST00000378891.9	c.1496_1508del	p.Pro499ArgfsTer146	frameshift_variant	14/15	1		A1
DVL1	ENST00000631679.1	c.602_614del	p.Pro201ArgfsTer46	frameshift_variant	7/8	5
DVL1	ENST00000632445.1	c.500_512del	p.Pro167ArgfsTer46	frameshift_variant	4/6	5

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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant Robinow syndrome 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Feb 20, 2024	ACMG Criteria: PVS1, PS2, PM2, PP5; Variant was found in heterozygous state -
Likely pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Jun 01, 2017	- -

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: rs1553173420; hg19: chr1-1273487;