rs1554676454

Positions:

• chr7-74051978-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_000501.4(ELN):​c.944A>G​(p.Lys315Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ELN NM_000501.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.27

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a modified_residue Allysine (size 0) in uniprot entity ELN_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-74051978-A-G is Pathogenic according to our data. Variant chr7-74051978-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 524218.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELN	NM_000501.4	c.944A>G	p.Lys315Arg	missense_variant	17/33	ENST00000252034.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELN	ENST00000252034.12	c.944A>G	p.Lys315Arg	missense_variant	17/33	1	NM_000501.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Supravalvar aortic stenosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 02, 2023

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 315 of the ELN protein (p.Lys315Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a ELN-related disease (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 524218). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ELN protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T;.;T;T;.;.;.;.;.;T;.;.;.;.;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.52	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.8	.;.;L;L;.;.;.;L;.;.;.;.;.;.;L;L
MutationTaster	Benign	0.59	D;D;D;D;D;D;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.1	N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.31	T;.;T;T;T;D;D;.;T;T;T;T;D;.;T;T
Sift4G	Benign	0.52	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.96	D;D;D;.;D;.;D;D;D;D;D;D;D;D;D;.
Vest4		0.36
MutPred		0.31		.;.;.;.;.;.;.;.;Gain of methylation at K305 (P = 0.012);.;Gain of methylation at K305 (P = 0.012);.;.;.;.;.;
MVP		0.76
MPC		0.15
ClinPred		0.55	D
GERP RS		5.0
Varity_R		0.068
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.83		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554676454; hg19: chr7-73466308;