rs794726666

Positions:

• chr4-5804735-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_153717.3(EVC):​c.2457delG​(p.Met820fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EVC NM_153717.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.82

Genes affected

EVC (HGNC:3497): (EvC ciliary complex subunit 1) This gene encodes a protein containing a leucine zipper and a transmembrane domain. This gene has been implicated in both Ellis-van Creveld syndrome (EvC) and Weyers acrodental dysostosis. [provided by RefSeq, Jul 2008]

CRMP1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-5804735-AG-A is Pathogenic according to our data. Variant chr4-5804735-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 5344.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC	NM_153717.3	c.2457delG	p.Met820fs	frameshift_variant	17/21	ENST00000264956.11	NP_714928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC	ENST00000264956.11	c.2457delG	p.Met820fs	frameshift_variant	17/21	1	NM_153717.3	ENSP00000264956.6
CRMP1	ENST00000506216.5	n.1647+20758delC		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ellis-van Creveld syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2000

- -

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 31, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 5344). This variant is also known as 2456delG. This premature translational stop signal has been observed in individual(s) with Ellis-van Creveld syndrome (PMID: 10700184). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Met820Trpfs*108) in the EVC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EVC are known to be pathogenic (PMID: 23220543). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs794726666; hg19: chr4-5806462;