VCV000626330.5 - ClinVar

NM_003676.4(DEGS1):c.320G>A (p.Trp107Ter)

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.

(4)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003676.4(DEGS1):c.320G>A (p.Trp107Ter)

Variation ID: 626330 Accession: VCV000626330.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q42.11 1: 224189814 (GRCh38) [ NCBI UCSC ] 1: 224377516 (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	May 2, 2019	Feb 4, 2024	Jul 27, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_003676.4(DEGS1):c.320G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_003676.4:c.320G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003667.1:p.Trp107Ter	nonsense
NM_001321541.2:c.320G>A	NP_001308470.1:p.Trp107Ter	nonsense
NM_001321542.2:c.212G>A	NP_001308471.1:p.Trp71Ter	nonsense
NC_000001.11:g.224189814G>A
NC_000001.10:g.224377516G>A

... more HGVS ... less HGVS

Protein change

W107*, W71*

Other names

Canonical SPDI

NC_000001.11:224189813:G:A

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

OMIM: 615843.0007 dbSNP: rs1382083552 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.
DEGS1		-	-	GRCh38 GRCh37	76	117

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.
Leukodystrophy, hypomyelinating, 18	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jul 27, 2022	RCV000768574.7

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 (Sep 25, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Leukodystrophy, hypomyelinating, 18 Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV001146810.1 First in ClinVar: Jan 20, 2020 Last updated: Jan 20, 2020	Publications: PubMed (1) PubMed: 30620337 Comment: This variant is interpreted as a Likely pathogenic for Leukodystrophy, hypomyelinating, 18, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PVS1-Strong.
Likely pathogenic (May 28, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Leukodystrophy, hypomyelinating, 18 (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001430792.1 First in ClinVar: Aug 23, 2020 Last updated: Aug 23, 2020	Publications: PubMed (1) PubMed: 30620337 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7105ec33-6939-48bb-9140-394074abe473 Comment: The homozygous p.Trp107Ter variant in DEGS1 was identified by our study in an individual with hypomyelinating leukodystrophy (PMID: 30620337). The p.Trp107Ter variant in DEGS1 has … (more) The homozygous p.Trp107Ter variant in DEGS1 was identified by our study in an individual with hypomyelinating leukodystrophy (PMID: 30620337). The p.Trp107Ter variant in DEGS1 has also been reported in 3 additional individuals with hypomyelinating leukodystrophy, segregated with disease in 3 affected relatives from 1 family (PMID: 30620337), and has been identified in 0.003% (1/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1382083552). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported pathogenic by OMIM in ClinVar (Variation ID: 626330). The presence of this variant in 4 affected homozygotes increases the likelihood that the p.Trp107Ter variant is pathogenic (PMID: 30620337). This nonsense variant leads to a premature termination codon at position 107, which is predicted to lead to a truncated or absent protein. While there is some evidence to suggest that loss of function of the DEGS1 gene is a disease mechanism in autosomal recessive hypomyelinating leukodystrophy, this association is not yet strongly established based on the criteria laid out in Tayoun, 2018 (PMID: 30192042). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_Strong, PM2, PM3, PP1 (Richards 2015). (less)
Pathogenic (Jul 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leukodystrophy, hypomyelinating, 18 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003827526.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Apr 30, 2019)	no assertion criteria provided Method: literature only	LEUKODYSTROPHY, HYPOMYELINATING, 18 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000899278.1 First in ClinVar: May 02, 2019 Last updated: May 02, 2019	Publications: PubMed (1) PubMed: 30620337 Comment on evidence: In 3 sibs (patients 11, 12, and 13), born of consanguineous Egyptian parents (family 8), with hypomyelinating leukodystrophy-18 (HLD18; 618404), Pant et al. (2019) identified … (more) In 3 sibs (patients 11, 12, and 13), born of consanguineous Egyptian parents (family 8), with hypomyelinating leukodystrophy-18 (HLD18; 618404), Pant et al. (2019) identified a homozygous c.320G-A transition (c.320G-A, NM_003676.3) in exon 2 of the DEGS1 gene, resulting in a trp107-to-ter (W107X) substitution. An unrelated patient (patient 18), also born of consanguineous Egyptian parents (family 12), was found to carry the same homozygous mutation. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was shown to segregate with the disorder in family 8. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a loss of function. The patients were severely affected; 2 sibs in the first family died before 5 years of age. (less)

Comment:

The homozygous p.Trp107Ter variant in DEGS1 was identified by our study in an individual with hypomyelinating leukodystrophy (PMID: 30620337). The p.Trp107Ter variant in DEGS1 has also been reported in 3 additional individuals with hypomyelinating leukodystrophy, segregated with disease in 3 affected relatives from 1 family (PMID: 30620337), and has been identified in 0.003% (1/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1382083552). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported pathogenic by OMIM in ClinVar (Variation ID: 626330). The presence of this variant in 4 affected homozygotes increases the likelihood that the p.Trp107Ter variant is pathogenic (PMID: 30620337). This nonsense variant leads to a premature termination codon at position 107, which is predicted to lead to a truncated or absent protein. While there is some evidence to suggest that loss of function of the DEGS1 gene is a disease mechanism in autosomal recessive hypomyelinating leukodystrophy, this association is not yet strongly established based on the criteria laid out in Tayoun, 2018 (PMID: 30192042). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_Strong, PM2, PM3, PP1 (Richards 2015).

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
Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy.	Pant DC	The Journal of clinical investigation	2019	PMID: 30620337
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7105ec33-6939-48bb-9140-394074abe473	-	-	-	-

Text-mined citations for rs1382083552 ...

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 Mar 30, 2024

ClinVar Genomic variation as it relates to human health

NM_003676.4(DEGS1):c.320G>A (p.Trp107Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1382083552 ...