rs397516433

Variant names:

• chr7-74051747-C-G
• rs397516433
• NM_000501.4:c.800-3C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-74051747-C-G
• chr7-74051747-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000501.4(ELN):​c.800-3C>G variant causes a splice region, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ELN NM_000501.4 splice_region, intron
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.33
• Publications: 4 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 Gene-Disease associations (from GenCC):

• cutis laxa, autosomal dominant 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Genomics England PanelApp, G2P
• supravalvular aortic stenosis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• autosomal dominant cutis laxa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-74051747-C-G is Pathogenic according to our data. Variant chr7-74051747-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 43586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELN	NM_000501.4	c.800-3C>G		splice_region_variant, intron_variant	Intron 15 of 32	ENST00000252034.12	NP_000492.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELN	ENST00000252034.12	c.800-3C>G		splice_region_variant, intron_variant	Intron 15 of 32	1	NM_000501.4	ENSP00000252034.7

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:4

Jul 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 15 of the ELN gene. It does not directly change the encoded amino acid sequence of the ELN protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with supravalvular aortic stenosis (PMID: 9215670, 10190324). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS15-3C>G. ClinVar contains an entry for this variant (Variation ID: 43586). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.

Jul 21, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 800-3C>G variant has been reported in 3 families with SVAS and segregated wi th disease in >10 affected individuals (Li 1997, Urban 1999). The variant was no t detected in over 900 control chromosomes, supporting a pathogenic role (Li 199 7, Urban 1999). This variant is located in the 3' splice region and although it does not affect the highly conserved -1 and -2 positions, molecular studies show ed abnormal splicing and skipping of exon 16 (Urban 1999, Wachi 2007). In summar y, the 800-3C>G variant meets our criteria for pathogenicity (http://pcpgm.partn ers.org/lmm) based on the severity of the change, segregation with disease, func tional studies, and absence from controls.

Feb 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jun 30, 2025

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ELN c.800-3C>G variant (also known as IVS15-3C>G) has been observed in individuals with supravalvular aortic stenosis and segregates with disease (Li DY et al., PMID: 9215670; Urban Z et al., PMID: 10190324). Two different studies performed functional analysis on patient fibroblasts. Wachi and colleagues demonstrated that this variant causes skipping of exons 16-17 and results in stable mRNA (Wachi H et al., PMID: 17037986). They further concluded that tropolastin lacking these exons results in reduced self-association and altered elastic fiber formation. Conversely, Urban and colleagues showed generation of a cryptic splice that would lead to a frameshift and reduced expression, indicating haploinsufficiency (Urban Z et al., PMID: 10190324). This variant is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. Computational predictors indicate that this variant would alter splicing, evidence that correlates to an impact of this variant on ELN function. This variant has been reported in the ClinVar database as a pathogenic variant by five submitters (ClinVar Variation ID: 43586). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

Inborn genetic diseases Pathogenic:1

Feb 26, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The alteration results in an intronic change: _x000D_ _x000D_ The c.800-3C>G intronic alteration results from a C to G substitution 3 nucleotides before coding exon 16 of the ELN gene. The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the ELN c.800-3C>G alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals: _x000D_ _x000D_ The ELN c.800-3C>G alteration (also referred to as IVIS15-3C>G) has been reported to segregate with supravalvular aortic stenosis in at least three unrelated families (Li, 1997; Urban, 1999). The altered nucleotide is conserved throughout evolution:_x000D_ _x000D_ The c.800-3C nucleotide is conserved in available vertebrate species. Molecular analysis reveals aberrant splicing from this alteration:_x000D_ _x000D_ Using mRNA studies, Urbán et al. (1999) and Wachi et al. (2007) demonstrated that c.800-3C>G alteration leads to aberrant splicing and exon skipping in the ELN gene. Additional studies by Wachi et al. (2007) showed that this aberrantly spliced transcript was able to synthesize a stable polypeptide that could interact with fibrillin-1 and fibulin-5 proteins, but was deficient in forming homotypic interactions. The alteration is predicted to affect splicing by in silico models:_x000D_ _x000D_ Based on BDGP and ESEfinder splice site in silico tools, this alteration is predicted to abolish the native splice acceptor site and is supported by molecular studies (see above). Based on the available evidence, this alteration is classified as pathogenic.

not provided Pathogenic:1

Feb 17, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Non-canonical splice site variant predicted to destroy the natural splice acceptor site in intron 15; Published functional studies demonstrate the production of aberrant mRNA lacking exons 16 and 17 in skin fibroblasts of affected individuals (Wachi et al., 2007); Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 11175284, 17037986, 10190324, 9215670)

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	26
DANN	Benign	0.94
PhyloP100		2.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.90		Position offset: -41
DS_AL_spliceai		0.90		Position offset: 3

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

Other links and lift over

dbSNP: rs397516433; hg19: chr7-73466077;