VCV001048758.2 - ClinVar

NM_001128636.4(ELFN1):c.42_49del (p.Ala15fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(1)

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001128636.4(ELFN1):c.42_49del (p.Ala15fs)

Variation ID: 1048758 Accession: VCV001048758.2

Type and length

Deletion, 8 bp

Location

Cytogenetic: 7p22.3 7: 1744638-1744645 (GRCh38) [ NCBI UCSC ] 7: 1784274-1784281 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 13, 2021	Nov 11, 2021	Nov 4, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_001128636.4:c.42_49del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001122108.1:p.Ala15fs	frameshift
NM_001128636.2:c.42_49del
NM_001394187.1:c.42_49del	NP_001381116.1:p.Ala15fs	frameshift
NM_001394188.1:c.42_49del	NP_001381117.1:p.Ala15fs	frameshift
NC_000007.14:g.1744638_1744645del
NC_000007.13:g.1784274_1784281del

... more HGVS ... less HGVS

Protein change

A15fs

Other names

Canonical SPDI

NC_000007.14:1744637:GGCCGCCA:

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 614964.0001 dbSNP: rs2128605586 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ELFN1		-	-	GRCh38 GRCh37	103	157

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Developmental and Epileptic Encephalopathy with Joint Laxity	Likely pathogenic (1)	no assertion criteria provided	Jan 3, 2020	RCV001353345.1
not provided	Uncertain significance (1)	no assertion criteria provided	Nov 4, 2021	RCV001775169.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Jan 03, 2020)	no assertion criteria provided Method: clinical testing	Developmental and Epileptic Encephalopathy with Joint Laxity (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Hacettepe Dept. of Bioinformatics Rare Diseases Research Center, Institute of Health Sciences Accession: SCV001548241.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Publications: PubMed (1) PubMed: 24312227 Comment: The c.42_49delGGCCGCCA: p.(Ala15Profs241) in exon 2 (GRCh37, NM_001128636.2) of ELFN1 has not been reported previously in the literature. Molecular analysis confirmed homozygosity for a novel … (more) The c.42_49delGGCCGCCA: p.(Ala15Profs241) in exon 2 (GRCh37, NM_001128636.2) of ELFN1 has not been reported previously in the literature. Molecular analysis confirmed homozygosity for a novel variant, c.42_49delGGCCGCCA: p.(Ala15Profs241) in exon 2 of ELFN1. Sanger sequencing revealed that father and mother were both heterozygous carriers for the p.(Ala15Profs241 ) variant in ELFN1. Sanger sequencing showed his younger sister was also homozygous for this rare variant. This genetic alteration was predicted as Disease-Causing by MutationTaster (with a score of 1.0). This genetic change was not present in our in-house database which comprises 410 clinically unrelated Turkish individuals. In summary, the p.(Ala15Profs*241) variant meets our criteria to be classified as likely pathogenic. Besides, Elfn1 mutations in mice were previously associated with seizures and hyperactivity (Dolan 2013). (less) Clinical Features: Seizure (present) , High palate (present) , Joint laxity (present) , Axial hypotonia (present) , Poor head control (present) , Strabismus (present) Age: 10-19 years Sex: male Ethnicity/Population group: Turkish Geographic origin: Turkey
Uncertain significance (Nov 04, 2021)	no assertion criteria provided Method: literature only	VARIANT OF UNKNOWN SIGNIFICANCE Affected status: not provided Allele origin: germline	OMIM Accession: SCV002011841.1 First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021	Publications: PubMed (1) PubMed: 34509675 Comment on evidence: This variant is classified as a variant of unknown significance because its contribution to developmental and epileptic encephalopathy (see, e.g., DEE1, 308350) has not been … (more) This variant is classified as a variant of unknown significance because its contribution to developmental and epileptic encephalopathy (see, e.g., DEE1, 308350) has not been confirmed. In 3 sibs, born of consanguineous Turkish parents, with an undefined developmental and epileptic encephalopathy, Dursun et al. (2021) identified a homozygous 8-bp deletion (c.42_49del, NM_001128636.2) in the ELFN1 gene, predicted to result in a frameshift and premature termination (Ala15ProfsTer241) in the signal peptide domain. The variant, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not present in the gnomAD database. Patient cells showed about a 52% reduction in ELFN1 mRNA compared to controls, but additional functional studies of the variant were not performed. Variant sequencing identified a second candidate alteration (c.215G-T, NM_005806.3; Gly72Val) in the OLIG2 gene (606386) on chromosome 21q22 that may have contributed to the phenotype, but further analysis of OLIG2 was not done. The patients presented with profound global developmental delay, impaired intellectual development, autistic features, early infantile refractory epileptic encephalopathy, pyramidal signs, joint laxity, and facial dysmorphism. Other features included truncal hypotonia, inability to walk, absent speech, poor eye contact, and poor overall growth. Dysmorphic facial features included deep-set eyes, large ears, wide mouth, long philtrum, strabismus, and exotropia. Brain imaging in the 2 older sibs showed prominent cerebellar fissures and thin corpus callosum. (less)

Comment:

The c.42_49delGGCCGCCA: p.(Ala15Profs*241) in exon 2 (GRCh37, NM_001128636.2) of ELFN1 has not been reported previously in the literature. Molecular analysis confirmed homozygosity for a novel variant, c.42_49delGGCCGCCA: p.(Ala15Profs*241) in exon 2 of ELFN1. Sanger sequencing revealed that father and mother were both heterozygous carriers for the p.(Ala15Profs*241 ) variant in ELFN1. Sanger sequencing showed his younger sister was also homozygous for this rare variant. This genetic alteration was predicted as Disease-Causing by MutationTaster (with a score of 1.0). This genetic change was not present in our in-house database which comprises 410 clinically unrelated Turkish individuals. In summary, the p.(Ala15Profs*241) variant meets our criteria to be classified as likely pathogenic. Besides, Elfn1 mutations in mice were previously associated with seizures and hyperactivity (Dolan 2013).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Biallelic mutations in ELFN1 gene associated with developmental and epileptic encephalopathy and joint laxity.	Dursun A	European journal of medical genetics	2021	PMID: 34509675
Mutation of Elfn1 in mice causes seizures and hyperactivity.	Dolan J	PloS one	2013	PMID: 24312227

Text-mined citations for rs2128605586 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 25, 2023

ClinVar Genomic variation as it relates to human health

NM_001128636.4(ELFN1):c.42_49del (p.Ala15fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2128605586 ...