VCV000988780.3 - ClinVar

NM_000147.5(FUCA1):c.662_662+8del

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.

(2)

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_000147.5(FUCA1):c.662_662+8del

Variation ID: 988780 Accession: VCV000988780.3

Type and length

Deletion, 9 bp

Location

Cytogenetic: 1p36.11 1: 23863126-23863134 (GRCh38) [ NCBI UCSC ] 1: 24189616-24189624 (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	Jan 17, 2021	Feb 14, 2024	Dec 5, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000147.5:c.662_662+8del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NC_000001.11:g.23863129_23863137del
NC_000001.10:g.24189619_24189627del
NG_013346.1:g.10233_10241del
NG_013346.1:g.10236_10244del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000001.11:23863125:TGTCTTACCTGT:TGT

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

variation affecting protein structure; Variation Ontology [ VariO:0060]

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

dbSNP: rs766794815 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.
FUCA1		-	-	GRCh38 GRCh37	363	444

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.
Fucosidosis	Likely pathogenic (2)	criteria provided, single submitter	Dec 5, 2023	RCV001281353.12

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 (Dec 05, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Fucosidosis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004281630.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 16199547‚ 10094192 Comment: This variant results in the deletion of part of exon 3 (c.662_662+8del) of the FUCA1 gene. It is expected to disrupt RNA splicing. Variants that … (more) This variant results in the deletion of part of exon 3 (c.662_662+8del) of the FUCA1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FUCA1 are known to be pathogenic (PMID: 10094192). This variant is present in population databases (rs766794815, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with FUCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 988780). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
Likely pathogenic (Dec 11, 2020)	no assertion criteria provided Method: research	Fucosidosis (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Laboratory of Genomics, National Research Institute of Animal Production Accession: SCV001450462.1 First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021	Comment: 9-base-pair deletion (NG_013346.1:g.10233-10241delACAGGTAAG) covering the junction between exon 3 (4 bases) and intron 3 (5 bases) within FUCA1 sequence was associated with fucosidosis. This homozygous … (more) 9-base-pair deletion (NG_013346.1:g.10233-10241delACAGGTAAG) covering the junction between exon 3 (4 bases) and intron 3 (5 bases) within FUCA1 sequence was associated with fucosidosis. This homozygous deletion was identified in the 5-year-old girl with clinical suspicion of fucosidosis and was associated with 2.6-fold decrease in alpha-L-fucosidase activity in her whole blood samples (17.89 nmol/mg protein/hour [N: 46 +/- 4]). Parents of the child are heterozygous for mentioned deletion. (less) Age: 0-9 years Sex: female Method: DNA was isolated from whole blood. Sample set included persons of family trio and the blood of single unrelated person. PCR assay encompassed amplification of nine DNA fragments covering exons in the region of 23319 bp of FUCA1 reference sequence (chr1:23845077-23844894 from GRCh38 version of the human genome). Amplification were performed using hot start Taq DNA polymerase (Qiagen). Thermal program included initial step of 95oC for 15 minutes, 30 cycles of denaturation at 94oC for 30 sec., 1 min. of annealing and 1 min. of extension at 72oC, and final extension step at 72oC for 7 min. In case of primers designed for the region of exon 5 touchdown PCR procedure (TDPCR) were applied in the first stage of amplification. Initial TDPCR stage included 11 steps of annealing temperature decrease of 0.5oC in the range from 65oC down to 59.5oC. The second stage of TDPCR included 30 PCR cycles with annealing at 59oC. PCR amplifications were done on the VeritiPro Thermal Cycler. Amplified DNA samples were run in two percent agarose gel stained with ethidium bromide. Products revealing clear PCR bands were subjected to Sanger sequencing using PCR primers and BigDyeâ„¢ Terminator v3.1 Cycle Sequencing Kit (Thermofisher Scientific). The manufacturer recommended cycle sequencing program were applied with the primer annealing of 59oC and 4 minutes of extension at 60oC. Sequencing of PCR products were done on the VeritiPro Thermal Cycler (Thermofisher Scientific). Sequencing products were cleaned with the BigDye XTerminatorâ„¢ Purification Kit (Thermofisher Scientific) and electrophoresed on the ABI3500xl genetic analyzer (Thermo Fisher Scientific). Obtained sequencing traces were evaluated for the quality and subjected to variant genotyping using FinchTV 1.4.0 (Geospiza Inc.) and Variant Analysis (VA) software (Applied Biosystems). Obtained sequence traces were aligned against reference sequence of the human genome using blastx option of NCBI web site in order to check for their homology to the translated sequences encoding FUCA1 protein isoforms.

Comment:

This variant results in the deletion of part of exon 3 (c.662_662+8del) of the FUCA1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FUCA1 are known to be pathogenic (PMID: 10094192). This variant is present in population databases (rs766794815, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with FUCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 988780). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

9-base-pair deletion (NG_013346.1:g.10233-10241delACAGGTAAG) covering the junction between exon 3 (4 bases) and intron 3 (5 bases) within FUCA1 sequence was associated with fucosidosis. This homozygous deletion was identified in the 5-year-old girl with clinical suspicion of fucosidosis and was associated with 2.6-fold decrease in alpha-L-fucosidase activity in her whole blood samples (17.89 nmol/mg protein/hour [N: 46 +/- 4]). Parents of the child are heterozygous for mentioned deletion.

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.
variation affecting protein structure (VariO:0060)	DNA was isolated from whole blood. Sample set included persons of family trio and the blood of single unrelated person. PCR assay encompassed amplification of nine DNA fragments covering exons in the region of 23319 bp of FUCA1 reference sequence (chr1:23845077-23844894 from GRCh38 version of the human genome). Amplification were performed using hot start Taq DNA polymerase (Qiagen). Thermal program included initial step of 95oC for 15 minutes, 30 cycles of denaturation at 94oC for 30 sec., 1 min. of annealing and 1 min. of extension at 72oC, and final extension step at 72oC for 7 min. In case of primers designed for the region of exon 5 touchdown PCR procedure (TDPCR) were applied in the first stage of amplification. Initial TDPCR stage included 11 steps of annealing temperature decrease of 0.5oC in the range from 65oC down to 59.5oC. The second stage of TDPCR included 30 PCR cycles with annealing at 59oC. PCR amplifications were done on the VeritiPro Thermal Cycler. Amplified DNA samples were run in two percent agarose gel stained with ethidium bromide. Products revealing clear PCR bands were subjected to Sanger sequencing using PCR primers and BigDyeâ„¢ Terminator v3.1 Cycle Sequencing Kit (Thermofisher Scientific). The manufacturer recommended cycle sequencing program were applied with the primer annealing of 59oC and 4 minutes of extension at 60oC. Sequencing of PCR products were done on the VeritiPro Thermal Cycler (Thermofisher Scientific). Sequencing products were cleaned with the BigDye XTerminatorâ„¢ Purification Kit (Thermofisher Scientific) and electrophoresed on the ABI3500xl genetic analyzer (Thermo Fisher Scientific). Obtained sequencing traces were evaluated for the quality and subjected to variant genotyping using FinchTV 1.4.0 (Geospiza Inc.) and Variant Analysis (VA) software (Applied Biosystems). Obtained sequence traces were aligned against reference sequence of the human genome using blastx option of NCBI web site in order to check for their homology to the translated sequences encoding FUCA1 protein isoforms.	Result not provided	Laboratory of Genomics, National Research Institute of Animal Production Accession: SCV001450462.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
Spectrum of mutations in fucosidosis.	Willems PJ	European journal of human genetics : EJHG	1999	PMID: 10094192

Text-mined citations for rs766794815 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000147.5(FUCA1):c.662_662+8del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs766794815 ...