7-74056680-C-T

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.1324C>T(p.Gln442Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ELN NM_000501.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.74

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 7-74056680-C-T is Pathogenic according to our data. Variant chr7-74056680-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-74056680-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELN	NM_000501.4	c.1324C>T	p.Gln442Ter	stop_gained	21/33	ENST00000252034.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELN	ENST00000252034.12	c.1324C>T	p.Gln442Ter	stop_gained	21/33	1	NM_000501.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Supravalvar aortic stenosis Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 04, 2011	The Gln442X variant has been reported in 4 individuals with both sporadic and fa milial SVAS (Li 1997, Metcalfe 2000). In addition, this variant was absent from over 750 control chromosomes (Li 1997), supporting a pathogenic role. Furthermor e, the Gln442X variant it leads to a premature stop at codon 442 and is predicte d to lead to a truncated or absent protein. Loss of function is an established mechanism of disease for the ELN gene (Human Gene Mutation Database, HGMD). Ther efore, the Gln442X variant meets our criteria for pathogenicity (http://pcpgm.pa rtners.org/lmm) and is highly likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 16722). This premature translational stop signal has been observed in individual(s) with clinical features of ELN-related conditions (PMID: 9215670). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln442*) in the ELN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ELN are known to be pathogenic (PMID: 11175284). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	KardioGenetik, Herz- und Diabeteszentrum NRW	Mar 18, 2024	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 11, 2022

Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 9215671, 9215670, 32960096, 27535533, 26582918, 11175284) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	37
Dann	Uncertain	0.99
Eigen	Uncertain	0.24
Eigen_PC	Benign	-0.057
FATHMM_MKL	Benign	0.24	N
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A;A;A;A
Vest4		0.71
GERP RS		2.0

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: rs137854452; hg19: chr7-73471010; COSMIC: COSV52715007; COSMIC: COSV52715007;