VCV002584877.1 - ClinVar

NM_001098672.2(HEPHL1):c.641_644dup (p.Tyr215Ter)

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.

(1)

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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001098672.2(HEPHL1):c.641_644dup (p.Tyr215Ter)

Variation ID: 2584877 Accession: VCV002584877.1

Type and length

Duplication, 4 bp

Location

Cytogenetic: 11q21 11: 94064339-94064340 (GRCh38) [ NCBI UCSC ] 11: 93797505-93797506 (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	Oct 28, 2023	Oct 28, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001098672.2:c.641_644dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001092142.1:p.Tyr215Ter	nonsense
NC_000011.10:g.94064343_94064346dup
NC_000011.9:g.93797509_93797512dup

Protein change

Y215*

Other names

Canonical SPDI

NC_000011.10:94064339:ATAGATA:ATAGATAGATA

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

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.
HEPHL1		-	-	GRCh38 GRCh37	122	140

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.
Pili torti-developmental delay-neurological abnormalities syndrome	Likely pathogenic (1)	criteria provided, single submitter	-	RCV003340777.3

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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pili torti-developmental delay-neurological abnormalities syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004047491.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: The frameshift variant c.641_644dup (p.Tyr215Ter) in HEPHL1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. … (more) The frameshift variant c.641_644dup (p.Tyr215Ter) in HEPHL1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Phe370MetfsTer57 variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has not been reported to the ClinVar database. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. The observed variant is not detected in the spouse. (less) Clinical Features: Abnormal heart morphology (present) , Abnormality of the thyroid gland (present) , Abnormality of limbs (present) , Miscarriage (present) , Absent fetal nasal bone (present) … (more) Abnormal heart morphology (present) , Abnormality of the thyroid gland (present) , Abnormality of limbs (present) , Miscarriage (present) , Absent fetal nasal bone (present) , Cystic hygroma (present) (less)

Comment:

The frameshift variant c.641_644dup (p.Tyr215Ter) in HEPHL1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Phe370MetfsTer57 variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has not been reported to the ClinVar database. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. The observed variant is not detected in the spouse.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Apr 06, 2024

ClinVar Genomic variation as it relates to human health

NM_001098672.2(HEPHL1):c.641_644dup (p.Tyr215Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...