7-74028189-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000501.4(ELN):​c.2T>C​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Consequence

ELN
NM_000501.4 start_lost

Scores

7
5
4

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.84
Variant links:
Genes affected
ELN (HGNC:3327): (elastin) This gene encodes a protein that is one of the two components of elastic fibers. Elastic fibers comprise part of the extracellular matrix and confer elasticity to organs and tissues including the heart, skin, lungs, ligaments, and blood vessels. The encoded protein is rich in hydrophobic amino acids such as glycine and proline, which form mobile hydrophobic regions bounded by crosslinks between lysine residues. Degradation products of the encoded protein, known as elastin-derived peptides or elastokines, bind the elastin receptor complex and other receptors and stimulate migration and proliferation of monocytes and skin fibroblasts. Elastokines can also contribute to cancer progression. Deletions and mutations in this gene are associated with supravalvular aortic stenosis (SVAS) and autosomal dominant cutis laxa. [provided by RefSeq, Aug 2017]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-74028189-T-C is Pathogenic according to our data. Variant chr7-74028189-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 213185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ELNNM_000501.4 linkuse as main transcriptc.2T>C p.Met1? start_lost 1/33 ENST00000252034.12 NP_000492.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ELNENST00000252034.12 linkuse as main transcriptc.2T>C p.Met1? start_lost 1/331 NM_000501.4 ENSP00000252034 P4P15502-2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Supravalvar aortic stenosis Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 24, 2020The p.Met1? in ELN has been reported in 2 family members with peripheral pulmonary stenosis, supravalvular aortic stenosis, and severe pulmonary emphysema (Louw 2012 PubMed: 22740173) and was absent from large population studies. This variant is listed in ClinVar (allele ID: 209907). This variant affects the translation initiation start codon (ATG). Since no other in-frame methionine is present in the elastin mRNA, this variant is predicted to lead to the absence of the elastin protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP Criteria applied: PM2, PVS1_Strong, PS4_Supporting. -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 03, 2023This sequence change affects the initiator methionine of the ELN mRNA. There are no downstream in-frame methionine residues; therefore, it is expected to result in an absent or disrupted protein product. Loss-of-function variants in ELN are known to be pathogenic (PMID: 9215670, 11175284). This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with syndromic structural heart defects (PMID: 10942104, 22740173). ClinVar contains an entry for this variant (Variation ID: 213185). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 12, 2024Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35741248, 28574231, 22740173) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.16
CADD
Uncertain
23
DANN
Benign
0.97
DEOGEN2
Benign
0.17
T;T;.;T;T;T;.;T;.;.;.;.;T;.;.;.;.;.;.;T;.
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.90
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.95
D
MetaRNN
Pathogenic
0.81
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.16
D
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PROVEAN
Benign
-0.93
N;.;N;N;N;N;N;D;N;N;N;N;N;N;D;N;N;N;N;D;N
REVEL
Pathogenic
0.68
Sift
Pathogenic
0.0
D;.;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;.;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.96
D;D;D;.;.;D;.;.;D;D;D;D;D;D;.;D;.;D;D;.;.
Vest4
0.87
MutPred
0.57
Gain of glycosylation at M1 (P = 0.0115);Gain of glycosylation at M1 (P = 0.0115);Gain of glycosylation at M1 (P = 0.0115);Gain of glycosylation at M1 (P = 0.0115);Gain of glycosylation at M1 (P = 0.0115);Gain of glycosylation at M1 (P = 0.0115);Gain of glycosylation at M1 (P = 0.0115);Gain of glycosylation at M1 (P = 0.0115);Gain of glycosylation at M1 (P = 0.0115);Gain of glycosylation at M1 (P = 0.0115);Gain of glycosylation at M1 (P = 0.0115);Gain of glycosylation at M1 (P = 0.0115);Gain of glycosylation at M1 (P = 0.0115);Gain of glycosylation at M1 (P = 0.0115);Gain of glycosylation at M1 (P = 0.0115);Gain of glycosylation at M1 (P = 0.0115);Gain of glycosylation at M1 (P = 0.0115);Gain of glycosylation at M1 (P = 0.0115);Gain of glycosylation at M1 (P = 0.0115);Gain of glycosylation at M1 (P = 0.0115);Gain of glycosylation at M1 (P = 0.0115);
MVP
0.83
ClinPred
0.85
D
GERP RS
4.5
Varity_R
0.25
gMVP
0.46

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: rs863223518; hg19: chr7-73442519; API