VCV002969476.3 - ClinVar

NM_001033855.3(DCLRE1C):c.1978_1981dup (p.Leu661Ter)

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.

(3)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001033855.3(DCLRE1C):c.1978_1981dup (p.Leu661Ter)

Variation ID: 2969476 Accession: VCV002969476.3

Type and length

Duplication, 4 bp

Location

Cytogenetic: 10p13 10: 14908505-14908506 (GRCh38) [ NCBI UCSC ] 10: 14950504-14950505 (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	Feb 29, 2024	Aug 18, 2024	Mar 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001033855.3:c.1978_1981dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001029027.1:p.Leu661Ter	nonsense
NM_001033857.3:c.1618_1621dup	NP_001029029.1:p.Leu541Ter	nonsense
NM_001033858.3:c.1618_1621dup	NP_001029030.1:p.Leu541Ter	nonsense
NM_001289076.2:c.1633_1636dup	NP_001276005.1:p.Leu546Ter	nonsense
NM_001289077.2:c.1618_1621dup	NP_001276006.1:p.Leu541Ter	nonsense
NM_001289078.2:c.1633_1636dup	NP_001276007.1:p.Leu546Ter	nonsense
NM_001289079.2:c.1618_1621dup	NP_001276008.1:p.Leu541Ter	nonsense
NM_001350965.2:c.1782+196_1782+199dup		intron variant
NM_001350966.2:c.1437+196_1437+199dup		intron variant
NM_001350967.2:c.1422+196_1422+199dup		intron variant
NM_022487.4:c.1633_1636dup	NP_071932.2:p.Leu546Ter	nonsense
NR_110297.2:n.2417_2420dup		non-coding transcript variant
NR_146961.2:n.2158_2161dup		non-coding transcript variant
NR_146962.1:n.2465_2468dup		non-coding transcript variant
NC_000010.11:g.14908507_14908510dup
NC_000010.10:g.14950506_14950509dup
NG_007276.1:g.50587_50590dup
LRG_54:g.50587_50590dup
LRG_54t1:c.1977_1980dup	LRG_54p1:p.Leu661Terfs

... more HGVS ... less HGVS

Protein change

L546*, L541*, L661*

Other names

Canonical SPDI

NC_000010.11:14908505:ACTCA:ACTCACTCA

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.
DCLRE1C		-	-	GRCh38 GRCh37	1056	1105

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.
Severe combined immunodeficiency due to DCLRE1C deficiency	Uncertain significance (1)	criteria provided, single submitter	Jan 2, 2024	RCV003827146.2
not provided	Uncertain significance (1)	criteria provided, single submitter	-	RCV004696569.1
Histiocytic medullary reticulosis	Uncertain significance (1)	criteria provided, single submitter	Mar 4, 2024	RCV004573346.1

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.
Uncertain significance (Jan 02, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Severe combined immunodeficiency due to DCLRE1C deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004628585.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Comment: This sequence change creates a premature translational stop signal (p.Leu661) in the DCLRE1C gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Leu661) in the DCLRE1C gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acid(s) of the DCLRE1C protein. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Mar 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Histiocytic medullary reticulosis Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005059354.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005190646.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024

Comment:

This sequence change creates a premature translational stop signal (p.Leu661*) in the DCLRE1C gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acid(s) of the DCLRE1C protein. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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 Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_001033855.3(DCLRE1C):c.1978_1981dup (p.Leu661Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...