NM_000501.4(ELN):c.800-2A>G AND Supravalvar aortic stenosis

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 4, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000150636.11

Allele description [Variation Report for NM_000501.4(ELN):c.800-2A>G]

NM_000501.4(ELN):c.800-2A>G

Gene:

ELN:elastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q11.23

Genomic location:

Preferred name:

NM_000501.4(ELN):c.800-2A>G

HGVS:

NC_000007.14:g.74051748A>G
NG_009261.1:g.28652A>G
NG_111490.1:g.195A>G
NM_000501.4:c.800-2A>GMANE SELECT
NM_001081752.3:c.770-2A>G
NM_001081753.3:c.815-2A>G
NM_001081754.3:c.815-2A>G
NM_001081755.3:c.800-2A>G
NM_001278912.2:c.800-2A>G
NM_001278913.2:c.692-2A>G
NM_001278914.2:c.785-2A>G
NM_001278915.2:c.800-2A>G
NM_001278916.2:c.758-2A>G
NM_001278917.2:c.770-2A>G
NM_001278918.2:c.668-2A>G
NM_001278939.2:c.800-2A>G
NC_000007.13:g.73466078A>G
NM_000501.2:c.800-2A>G
NM_001278939.1:c.800-2A>G

Nucleotide change:

IVS15AS, A-G, -2

Links:

OMIM: 130160.0006; dbSNP: rs727503027

NCBI 1000 Genomes Browser:

rs727503027

Molecular consequence:

NM_000501.4:c.800-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001081752.3:c.770-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001081753.3:c.815-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001081754.3:c.815-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001081755.3:c.800-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001278912.2:c.800-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001278913.2:c.692-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001278914.2:c.785-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001278915.2:c.800-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001278916.2:c.758-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001278917.2:c.770-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001278918.2:c.668-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001278939.2:c.800-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

Observations:

Condition(s)

Name:: Supravalvar aortic stenosis (SVAS)
Synonyms:: Supravalvar aortic stenosis, Eisenberg type
Identifiers:: MONDO: MONDO:0008504; MedGen: C0003499; Orphanet: 3193; OMIM: 185500; Human Phenotype Ontology: HP:0004381

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000038484	OMIM	no assertion criteria provided	Pathogenic (Jul 1, 1997)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000197971	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (May 27, 2011)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9215670, 24033266
SCV000553216	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 4, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16199547, 11175284, 9215670, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000038484

OMIM

no assertion criteria provided

Pathogenic
(Jul 1, 1997)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000197971

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(May 27, 2011)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV000553216

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 4, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	1	1	not provided	not provided	not provided	literature only, clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000038484.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 2 unrelated kindreds, Li et al. (1997) found that SVAS (185500) segregated with an A-to-G transition at position -2 in the splice acceptor site of intron 15 preceding exon 16.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000197971.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

The 800-2A>G variant has been reported in 2 individuals with SVAS and was absent from more than 750 control chromosomes (Li 1997). In addition, this variant was observed to segregate with disease in 4 affected family members. Furthermore, t his variant is predicted to cause abnormal splicing because the nucleotide subst itution occurs in the highly conserved splice consensus sequence. Splice-site al terations are a reported cause of SVAS in the ELN gene (Human Gene Mutation Data base, HGMD). In summary, this variant meets our pathogenicity criteria (http://p cpgm.partners.org/LMM).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

From Invitae, SCV000553216.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change affects an acceptor splice site in intron 15 of the ELN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ELN are known to be pathogenic (PMID: 11175284). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with supravalvular aortic stenosis (PMID: 9215670). ClinVar contains an entry for this variant (Variation ID: 163387). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 28, 2024

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