rs863223518

Variant names:

• chr7-74028189-T-C
• rs863223518
• NM_000501.4:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 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
• Publications: 4 publications found

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]

ELN Gene-Disease associations (from GenCC):

• cutis laxa, autosomal dominant 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Genomics England PanelApp, G2P
• supravalvular aortic stenosis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• autosomal dominant cutis laxa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 213185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELN	NM_000501.4	c.2T>C	p.Met1?	start_lost	Exon 1 of 33	ENST00000252034.12	NP_000492.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELN	ENST00000252034.12	c.2T>C	p.Met1?	start_lost	Exon 1 of 33	1	NM_000501.4	ENSP00000252034.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.000267 Hom.: 0

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

Aug 24, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 29, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 35741248, 28574231, 39604264, 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
PhyloP100		3.8
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
PromoterAI		-0.36	Neutral
Varity_R		0.25
gMVP		0.46
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs863223518; hg19: chr7-73442519;