rs797044835

Positions:

• chr1-1338096-CA-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.1594del​(p.Trp532GlyfsTer142) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DVL1 NM_001330311.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.36

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. Fraction of 0.237 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-1338096-CA-C is Pathogenic according to our data. Variant chr1-1338096-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 208045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1338096-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DVL1	NM_001330311.2	c.1594del	p.Trp532GlyfsTer142	frameshift_variant	14/15	ENST00000378888.10	NP_001317240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DVL1	ENST00000378888.10	c.1594del	p.Trp532GlyfsTer142	frameshift_variant	14/15	5	NM_001330311.2	ENSP00000368166	P3
DVL1	ENST00000378891.9	c.1519del	p.Trp507GlyfsTer142	frameshift_variant	14/15	1		ENSP00000368169	A1
DVL1	ENST00000631679.1	c.625del	p.Trp209GlyfsTer42	frameshift_variant	7/8	5		ENSP00000488181
DVL1	ENST00000632445.1	c.523del	p.Trp175GlyfsTer42	frameshift_variant	4/6	5		ENSP00000488888

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant Robinow syndrome 2 Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). The variant has been reported as pathogenic/likely pathogenic without evidence for the classification (ClinVar ID: VCV000504195.6). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Sep 30, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 02, 2015	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 20, 2023

Frameshift variant predicted to result in protein truncation, as the last 164 amino acids are replaced with 141 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging gain of function effect (Bunn et al., 2015); This variant is associated with the following publications: (PMID: 30266093, 25817016, 25817014, 32888393, 33237614, 35047859) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs797044835; hg19: chr1-1273476;