NM_001286704.2(UFM1):c.-273_-271del AND Leukodystrophy, hypomyelinating, 14

Germline classification:: Pathogenic/Likely pathogenic (10 submissions)
Last evaluated:: Dec 12, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000585791.15

Allele description [Variation Report for NM_001286704.2(UFM1):c.-273_-271del]

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

Genes:

UFM1:ubiquitin fold modifier 1 [Gene - OMIM - HGNC]
LOC130009585:ATAC-STARR-seq lymphoblastoid active region 7595 [Gene]

Variant type:

Deletion

Cytogenetic location:

13q13.3

Genomic location:

Preferred name:

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

HGVS:

NC_000013.11:g.38349765_38349767del
NG_189164.1:g.265_267del
NM_001286704.2:c.-273_-271del
NC_000013.10:g.38923902_38923904del
NM_001286704.1:c.-273_-271del
NM_001286704.1:c.-273_-271delTCA
NM_016617.4:c.-155_-153delMANE SELECT
NM_016617.4:c.-155_-153delTCAMANE SELECT

Links:

OMIM: 610553.0001; dbSNP: rs747359907

NCBI 1000 Genomes Browser:

rs747359907

Molecular consequence:

NM_001286704.2:c.-273_-271del - upstream transcript variant - [Sequence Ontology: SO:0001986]

Functional consequence:

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

Observations:

Condition(s)

Name:: Leukodystrophy, hypomyelinating, 14
Identifiers:: MONDO: MONDO:0033486; MedGen: C4693535; OMIM: 617899

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000693707	OMIM	no assertion criteria provided	Pathogenic (Mar 6, 2018)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001366290	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 28, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001426650	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 32860008
SCV001984793	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 30, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002543809	Suma Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002577597	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 9, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002787933	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 21, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004034081	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34573312, 25741868
SCV004100794	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 13, 2023)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004175721	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 12, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

UFM1 founder mutation in the Roma population causes recessive variant of H-ABC.

Hamilton EMC, Bertini E, Kalaydjieva L, Morar B, Dojčáková D, Liu J, Vanderver A, Curiel J, Persoon CM, Diodato D, Pinelli L, van der Meij NL, Plecko B, Blaser S, Wolf NI, Waisfisz Q, Abbink TEM, van der Knaap MS; Recessive H-ABC Research Group..

Neurology. 2017 Oct 24;89(17):1821-1828. doi: 10.1212/WNL.0000000000004578. Epub 2017 Sep 20.

PubMed [citation]

PMID:: 28931644
PMCID:: PMC5664304

Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.

Bertoli-Avella AM, Beetz C, Ameziane N, Rocha ME, Guatibonza P, Pereira C, Calvo M, Herrera-Ordonez N, Segura-Castel M, Diego-Alvarez D, Zawada M, Kandaswamy KK, Werber M, Paknia O, Zielske S, Ugrinovski D, Warnack G, Kampe K, Iurașcu MI, Cozma C, Vogel F, Alhashem A, et al.

Eur J Hum Genet. 2021 Jan;29(1):141-153. doi: 10.1038/s41431-020-00713-9. Epub 2020 Aug 28.

PubMed [citation]

PMID:: 32860008
PMCID:: PMC7852664

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000693707.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001366290.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centogene AG - the Rare Disease Company, SCV001426650.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001984793.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Suma Genomics, SCV002543809.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV002577597.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

PS3, PM2, PP5

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002787933.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV004034081.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV004100794.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Criteria applied: PS3,PM3,PM2_SUP

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV004175721.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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