chr7-74060184-C-T

Position:

• chr7-74060184-C-T

Variant summary

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

The ENST00000252034.12(ELN):​c.1621C>T​(p.Arg541Ter) variant causes a stop gained, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ELN ENST00000252034.12 stop_gained, splice_region
• Scores: Splicing: ADA: 0.01750
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.417

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-AS1 (HGNC:40212): (ELN antisense RNA 1)

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 7-74060184-C-T is Pathogenic according to our data. Variant chr7-74060184-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELN	NM_000501.4	c.1621C>T	p.Arg541Ter	stop_gained, splice_region_variant	24/33	ENST00000252034.12	NP_000492.2
ELN-AS1	NR_183555.1	n.72-152G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELN	ENST00000252034.12	c.1621C>T	p.Arg541Ter	stop_gained, splice_region_variant	24/33	1	NM_000501.4	ENSP00000252034	P4
ELN-AS1	ENST00000435932.2	n.79-152G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Supravalvar aortic stenosis Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Nov 15, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	Feb 28, 2020	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 01, 2017

The c.1621C>T variant in the ELN gene has been reported previously in one newborn with severe cutis laxa, congenital pulmonary disease, supravalvular pulmonary artery stenosis, unilateral inguinal hernia and dysmorphic facial features (Graul-Neumann et al., 2008). The c.1621C>T variant alters the last (3') nucleotide of exon 24. mRNA studies using skin fibroblasts from the proband suggested that the variant abolished splicing from this exon/intron junction, resulting in in-frame skipping of this exon and expression of a protein lacking amino acids 526-540. The c.1621C>T variant was also present in this individual's unaffected father. However, expression studies using skin fibroblasts from the father showed that he had reduced expression of ELN mRNA, consistent with nonsense-mediated mRNA decay due to introduction of the R541X premature termination codon. The bases of this premature termination codon flank the intron and would only be present in an mRNA species that was spliced appropriately. The authors hypothesized that this potential difference in mRNA processing between father and son, while unexplained on a molecular/cellular level, may explain the highly variable clinical picture observed in this family (Graul- Neumann et al., 2008). The R541X variant has also been reported in association with supravalvular aortic stenosis (SVAS) in the absence of cutis laxa (reported as R570X in an alternate transcript of the ELN gene [Metcalfe et al., 2000; Li et al., 1997]). Metcalfe et al. reported R570X in one individual with sporadic, severe SVAS, peripheral pulmonary artery stenosis and bilateral inguinal hernias. Li et al. reported R570X in an individual with sporadic SVAS, and it was absent in >375 control samples. Functional studies were not performed in these cases. Other nonsense and splice site variants in the ELN gene have been reported in association with SVAS and cutis laxa. Furthermore, the c.1621C>T variants was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.1621 C>T in the ELN gene is interpreted as a disease-causing variant -

Cutis laxa, autosomal dominant 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 15, 2008

- -

ELN-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2022

The ELN c.1621C>T variant is predicted to result in premature protein termination (p.Arg541*). In an alternate transcript (NM_00127893.2) this variant is referred to as c.1708C>T (p.Arg570*). This variant has been reported in multiple individuals with ELN-related disease and in at least one individual it was reported to occur de novo (see for example - Li et al. 1997. PubMed ID: 9215670; Table S9 - Jin et al. 2017. PubMed ID: 28991257). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in ELN are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.32	N
M_CAP	Benign	0.027	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A;A;A;A
Vest4		0.80
GERP RS		1.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.018
dbscSNV1_RF	Benign	0.53
SpliceAI score (max)		0.010		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: rs137854453; hg19: chr7-73474514;