rs1553873969

Positions:

• chr4-5748262-G-GCAGC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_153717.3(EVC):​c.1056_1059dup​(p.Glu354SerfsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EVC NM_153717.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.596

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:2365): (collapsin response mediator protein 1) This gene encodes a member of a family of cytosolic phosphoproteins expressed exclusively in the nervous system. The encoded protein is thought to be a part of the semaphorin signal transduction pathway implicated in semaphorin-induced growth cone collapse during neural development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 4-5748262-G-GCAGC is Pathogenic according to our data. Variant chr4-5748262-G-GCAGC is described in ClinVar as [Pathogenic]. Clinvar id is 555774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC	NM_153717.3	c.1056_1059dup	p.Glu354SerfsTer31	frameshift_variant	8/21	ENST00000264956.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC	ENST00000264956.11	c.1056_1059dup	p.Glu354SerfsTer31	frameshift_variant	8/21	1	NM_153717.3	P1
EVC	ENST00000509451.1	c.1056_1059dup	p.Glu354SerfsTer31	frameshift_variant	8/12	1
CRMP1	ENST00000506216.5	n.1697_1698insGCTG		non_coding_transcript_exon_variant	13/13	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461884 Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ellis-van Creveld syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 28, 2017	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 13, 2018

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in EVC are known to be pathogenic (PMID: 23220543). This variant has been observed in two individuals affected with Ellis-van Creveld syndrome (PMID: 23220543). ClinVar contains an entry for this variant (Variation ID: 555774). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu354Serfs*31) in the EVC gene. It is expected to result in an absent or disrupted protein product. -

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: rs1553873969; hg19: chr4-5749989;