7-74028189-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.84

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000501.4 (ELN) was described as [Pathogenic] in ClinVar as 2735031
• 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	UniProt
ELN	NM_000501.4	c.2T>C	p.Met1?	start_lost	1/33	ENST00000252034.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELN	ENST00000252034.12	c.2T>C	p.Met1?	start_lost	1/33	1	NM_000501.4	P4

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

Submissions by phenotype

Supravalvar aortic stenosis Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 24, 2020	The 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 submitter	clinical testing	Invitae	Oct 03, 2023	This 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 submitter

clinical testing

GeneDx

Feb 09, 2023

Initiation 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

Other links and lift over

dbSNP: rs863223518; hg19: chr7-73442519;