Genetic Variant EVC:p.Lys252GlufsTer4 (chr4-5741760-T-TA) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_153717.3(EVC):c.752dupA(p.Lys252GlufsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000211 in 1,421,644 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: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

EVC
NM_153717.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 3.80

Publications

0 publications found

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]

EVC Gene-Disease associations (from GenCC):

acrofacial dysostosis, Weyers type
Inheritance: AD, Unknown, AR Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
Ellis-van Creveld syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health

EVC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 4-5741760-T-TA is Pathogenic according to our data. Variant chr4-5741760-T-TA is described in ClinVar as Pathogenic. ClinVar VariationId is 556656.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC	NM_153717.3 link	c.752dupA	p.Lys252GlufsTer4	frameshift_variant	Exon 6 of 21	ENST00000264956.11	NP_714928.1	P57679

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC	ENST00000264956.11 link	c.752dupA	p.Lys252GlufsTer4	frameshift_variant	Exon 6 of 21	1	NM_153717.3	ENSP00000264956.6		P57679
EVC	ENST00000509451.1 link	c.752dupA	p.Lys252GlufsTer4	frameshift_variant	Exon 6 of 12	1		ENSP00000426774.1		E9PCN4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000211

AC:

AN:

1421644

Hom.:

Cov.:

AF XY:

0.00000282

AC XY:

AN XY:

709244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32802

American (AMR)

AF:

0.00

AC:

AN:

44498

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25756

East Asian (EAS)

AF:

0.00

AC:

AN:

39350

South Asian (SAS)

AF:

0.00

AC:

AN:

84768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53256

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5320

European-Non Finnish (NFE)

AF:

0.00000279

AC:

AN:

1077002

Other (OTH)

AF:

0.00

AC:

AN:

58892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Ellis-van Creveld syndrome

Pathogenic:2

Feb 13, 2018

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Dec 23, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Pathogenic:1

Jun 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This premature translational stop signal has been observed in individual(s) with Ellis-van Creveld syndrome (PMID: 23220543). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 556656). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys252Glufs*4) 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

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.8

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over