rs727503028

Positions:

• chr7-74051808-T-TG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000501.4(ELN):​c.862dup​(p.Ala288GlyfsTer25) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P286P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ELN NM_000501.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.67

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 18 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 7-74051808-T-TG is Pathogenic according to our data. Variant chr7-74051808-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 163388.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.862dup	p.Ala288GlyfsTer25	frameshift_variant	16/33	ENST00000252034.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELN	ENST00000252034.12	c.862dup	p.Ala288GlyfsTer25	frameshift_variant	16/33	1	NM_000501.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 25, 2014

The c.862dupG mutation in the ELN gene causes a frameshift starting with codon Alanine 288, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 25 of the new reading frame, denoted p.Ala288GlyfsX25. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This mutation has not been previously reported to our knowledge. This variant was found in ELN -

Supravalvar aortic stenosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 07, 2012

The Ala288fs variant in ELN has not been previously reported in the literature n or previously identified by our laboratory. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 288 and lead t o a premature termination codon 25 amino acids downstream. This alteration is th en predicted to lead to a truncated or absent protein. Loss of function of the ELN gene is an established mechanism of disease in SVAS (Human Gene Mutation Dat abase, HGMD). In summary, the Ala288fs variant meets our criteria for pathogenic ity (http://pcpgm.partners.org/lmm). -

Computational scores

Source: dbNSFP v4.3

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: rs727503028; hg19: chr7-73466138;