rs755381180

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong

The NM_153717.3(EVC):​c.904_906delAAG​(p.Lys302del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.0000118 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

EVC
NM_153717.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 5.07
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_153717.3. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 4-5745302-AAAG-A is Pathogenic according to our data. Variant chr4-5745302-AAAG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5745302-AAAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EVCNM_153717.3 linkc.904_906delAAG p.Lys302del conservative_inframe_deletion Exon 7 of 21 ENST00000264956.11 NP_714928.1 P57679

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EVCENST00000264956.11 linkc.904_906delAAG p.Lys302del conservative_inframe_deletion Exon 7 of 21 1 NM_153717.3 ENSP00000264956.6 P57679
EVCENST00000509451.1 linkc.904_906delAAG p.Lys302del conservative_inframe_deletion Exon 7 of 12 1 ENSP00000426774.1 E9PCN4

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152172
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251470
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1461780
Hom.:
0
AF XY:
0.0000110
AC XY:
8
AN XY:
727214
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.0000126
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152172
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000162
Hom.:
0
Bravo
AF:
0.0000264

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Pathogenic:2
Jul 26, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 446661). This variant has been observed in individual(s) with Ellis-van Creveld syndrome (PMID: 10700184, 23220543, 29068549; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs755381180, gnomAD 0.005%). This variant, c.904_906del, results in the deletion of 1 amino acid(s) of the EVC protein (p.Lys302del), but otherwise preserves the integrity of the reading frame. -

Apr 14, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Short-rib thoracic dysplasia 6 with or without polydactyly Pathogenic:2
Jun 01, 2017
Dan Cohn Lab, University Of California Los Angeles
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

-
University of Washington Center for Mendelian Genomics, University of Washington
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Ellis-van Creveld syndrome Pathogenic:1
Aug 06, 2020
Natera, Inc.
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Pathogenic:1
Mar 14, 2023
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23220543, 18947413, 16404586, 29068549, 17024374, 19810119, 10700184) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs755381180; hg19: chr4-5747029; API