VCV000495149.37 - ClinVar

NM_001286704.2(UFM1):c.-273_-271del

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.

(13)

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_001286704.2(UFM1):c.-273_-271del

Variation ID: 495149 Accession: VCV000495149.37

Type and length

Deletion, 3 bp

Location

Cytogenetic: 13q13.3 13: 38923902-38923904 (GRCh37) [ NCBI UCSC ] 13: 38349765-38349767 (GRCh38) [ 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	Mar 9, 2018	Oct 20, 2024	Dec 12, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_016617.4:c.-155_-153del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_016617.4:c.-155_-153delTCA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001286704.1:c.-273_-271delTCA
NM_001286704.2:c.-273_-271del
NC_000013.11:g.38349765_38349767del
NC_000013.10:g.38923902_38923904del
NG_189164.1:g.265_267del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000013.11:38349764:TCA:

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

decreased transcript level variant; Sequence Ontology [ SO:0001541]

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) 0.00000

Links

ClinGen: CA248784013 OMIM: 610553.0001 dbSNP: rs747359907 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.
LOC130009585	-	-	-	GRCh38	-	29
UFM1		-	-	GRCh38 GRCh37	35	87

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, 14	Pathogenic/Likely pathogenic (10)	criteria provided, multiple submitters, no conflicts	Dec 12, 2023	RCV000585791.18
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Nov 1, 2022	RCV000782053.25

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.
Pathogenic (Sep 19, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes Accession: SCV000920521.1 First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leukodystrophy, hypomyelinating, 14 Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV001426650.1 First in ClinVar: Aug 09, 2020 Last updated: Aug 09, 2020	Publications: PubMed (1) PubMed: 32860008
Pathogenic (Nov 28, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leukodystrophy, hypomyelinating, 14 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001366290.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3. This variant was detected in homozygous state.
Likely pathogenic (Sep 30, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	LEUKODYSTROPHY, HYPOMYELINATING, 14 Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV001984793.1 First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021	Comment: This variant is located in the promoter region of UFM1 and has been previously reported as a homozygous change in sixteen patients with hypomyelination with … (more) This variant is located in the promoter region of UFM1 and has been previously reported as a homozygous change in sixteen patients with hypomyelination with atrophy of the basal ganglia and cerebellum (PMID: 28931644). Most of the patients were from Roma population, and the carrier frequency was as high as 25% in Eastern Slovakia (PMID: 28931644), suggesting a founder effect. In-vitro functional studies using a luciferase assay showed that this variant leads to reduced promoter activity in CNS-derived cell lines (PMID: 28931644). It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.-273_-271delTCA variant is classified as Likely Pathogenic. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leukodystrophy, hypomyelinating, 14 (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Suma Genomics, Suma Genomics Accession: SCV002543809.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022
Pathogenic (May 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leukodystrophy, hypomyelinating, 14 Affected status: yes Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV002577597.1 First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022	Comment: PS3, PM2, PP5
Pathogenic (Oct 21, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leukodystrophy, hypomyelinating, 14 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002787933.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Likely pathogenic (Sep 13, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leukodystrophy, hypomyelinating, 14 (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004100794.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023	Comment: Criteria applied: PS3,PM3,PM2_SUP Clinical Features: Developmental regression (present) , Hypotonia (present) , Short stature (present) , Severe global developmental delay (present) , Malnutrition (present) , Tetraplegia (present) , Spasticity (present) … (more) Developmental regression (present) , Hypotonia (present) , Short stature (present) , Severe global developmental delay (present) , Malnutrition (present) , Tetraplegia (present) , Spasticity (present) , Seizure (present) (less) Sex: female
Pathogenic (Dec 12, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leukodystrophy, hypomyelinating, 14 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV004175721.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Clinical Features: Microcephaly (present) , Hypotonia (present) , Respiratory insufficiency (present) , CNS hypomyelination (present)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leukodystrophy, hypomyelinating, 14 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV004034081.2 First in ClinVar: Sep 16, 2023 Last updated: Sep 01, 2024	Comment: Bi-allelic variants in UFM1 are associated with leukodystrophy, hypomyelinating, 14. Sex: female
Pathogenic (Nov 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001500592.21 First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024	Comment: UFM1: PM3:Very Strong, PM2 Number of individuals with the variant: 9
Pathogenic (Mar 06, 2018)	no assertion criteria provided Method: literature only	LEUKODYSTROPHY, HYPOMYELINATING, 14 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000693707.1 First in ClinVar: Mar 09, 2018 Last updated: Mar 09, 2018	Publications: PubMed (1) PubMed: 28931644 Comment on evidence: In 16 patients with hypomyelinating leukodystrophy-14 (HLD14; 617899), Hamilton et al. (2017) identified a homozygous 3-bp deletion in the promoter region of the UFM1 gene … (more) In 16 patients with hypomyelinating leukodystrophy-14 (HLD14; 617899), Hamilton et al. (2017) identified a homozygous 3-bp deletion in the promoter region of the UFM1 gene (c.-273_-271delTCA, NM_001286704.1). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Most of the patients were of Roma descent, and haplotype analysis indicated a founder effect. Screening of 670 Roma controls revealed 30 mutation carriers, yielding a carrier rate of 4.5% for the allele; 1 individual was homozygous for the mutation, but retrospective studies indicated that he was affected. Carrier rate in the specific community where the homozygous individual was from showed a carrier rate of about 25%. In vitro functional expression studies using a luciferase reporter in different cell lines showed that the mutation significantly reduced promoter and transcriptional activity in certain neuronal cell lines (SY5Y and U373), but not in other cell lines (HeLa and HOF-F2). (less)
Pathogenic (Apr 16, 2020)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: biparental	Molecular Genetics laboratory, Necker Hospital Accession: SCV004031350.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023	Clinical Features: Leukodystrophy (present)
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Comment:

This variant is located in the promoter region of UFM1 and has been previously reported as a homozygous change in sixteen patients with hypomyelination with atrophy of the basal ganglia and cerebellum (PMID: 28931644). Most of the patients were from Roma population, and the carrier frequency was as high as 25% in Eastern Slovakia (PMID: 28931644), suggesting a founder effect. In-vitro functional studies using a luciferase assay showed that this variant leads to reduced promoter activity in CNS-derived cell lines (PMID: 28931644). It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.-273_-271delTCA variant is classified as Likely Pathogenic.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
decreased transcript level variant (SO:0001541)			Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV004034081.2

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.	Bertoli-Avella AM	European journal of human genetics : EJHG	2021	PMID: 32860008
UFM1 founder mutation in the Roma population causes recessive variant of H-ABC.	Hamilton EMC	Neurology	2017	PMID: 28931644

Text-mined citations for rs747359907 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001286704.2(UFM1):c.-273_-271del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs747359907 ...