7-74060494-CG-C

Variant names:

• chr7-74060494-CG-C
• rs727503783
• NM_000501.4:c.1744delG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000501.4(ELN):​c.1744delG​(p.Ala582GlnfsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ELN NM_000501.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.24
• Publications: 3 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-AS1 (HGNC:40212): (ELN antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 7-74060494-CG-C is Pathogenic according to our data. Variant chr7-74060494-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 163395.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000501.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELN	NM_000501.4	MANE Select	c.1744delG	p.Ala582GlnfsTer31	frameshift	Exon 25 of 33	NP_000492.2
	ELN	NM_001278939.2		c.1831delG	p.Ala611GlnfsTer64	frameshift	Exon 26 of 34	NP_001265868.1
	ELN	NM_001278915.2		c.1762delG	p.Ala588GlnfsTer31	frameshift	Exon 25 of 33	NP_001265844.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELN	ENST00000252034.12	TSL:1 MANE Select	c.1744delG	p.Ala582GlnfsTer31	frameshift	Exon 25 of 33	ENSP00000252034.7
	ELN	ENST00000380562.8	TSL:1	c.1762delG	p.Ala588GlnfsTer31	frameshift	Exon 25 of 33	ENSP00000369936.4
	ELN	ENST00000458204.5	TSL:1	c.1714delG	p.Ala572GlnfsTer31	frameshift	Exon 24 of 32	ENSP00000403162.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Supravalvar aortic stenosis Pathogenic:1

Jul 28, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Ala582fs variant in ELN has not been reported in the literature nor previous ly been identified by our laboratory. This variant results in a frameshift begin ning at position 582. Two ELN mRNAs have been reported for this position and the Ala582fs variant creates a premature stop in both (31 amino acids downstream: N M_000501.2; 64 amino acids downstream: Tassabehji 1997). A premature stop codon at this position typically leads to mRNA degradation and therefore a heterozygou s loss of function, which is an established mechanism of disease for the ELN gen e (Human Gene Mutation Database, HGMD). Parental studies demonstrated de novo oc currence, which strongly supports a disease causing role.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=0/200	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: rs727503783; hg19: chr7-73474824;