VCV000000681.6 - ClinVar

NM_000147.5(FUCA1):c.1279C>T (p.Gln427Ter)

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.

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_000147.5(FUCA1):c.1279C>T (p.Gln427Ter)

Variation ID: 681 Accession: VCV000000681.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.11 1: 23845837 (GRCh38) [ NCBI UCSC ] 1: 24172327 (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	Apr 4, 2013	Feb 14, 2024	Jan 19, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000147.5:c.1279C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000138.2:p.Gln427Ter	nonsense
NC_000001.11:g.23845837G>A
NC_000001.10:g.24172327G>A
NG_013346.1:g.27533C>T

Protein change

Q427*

Other names

FUCA1, GLN351TER

Canonical SPDI

NC_000001.11:23845836: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.

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

ClinGen: CA114434 OMIM: 612280.0001 dbSNP: rs118204450 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 2642067 to determine the location of this allele on current reference sequence (Q427*).

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	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 19, 2024	RCV000000716.8

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 (Apr 06, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Fucosidosis Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000695634.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (3) PubMed: 10094192‚ 8401503‚ 9039984 Comment: Variant summary: The FUCA1 c.1279C>T (p.Gln427X) variant results in a premature termination codon, predicted to cause a truncated or absent FUCA1 protein due to nonsense … (more) Variant summary: The FUCA1 c.1279C>T (p.Gln427X) variant results in a premature termination codon, predicted to cause a truncated or absent FUCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/121354 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic FUCA1 variant (0.001118). This variant has been reported in multiple affected individuals with FUCO. In addition, the fibroblast from patients showed negligible enzyme activity and very low CRIM level for a-L-fucosidase (Seo_1993). Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Jan 19, 2024)	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: SCV002236332.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 8401503 Comment: This sequence change creates a premature translational stop signal (p.Gln427) in the FUCA1 gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Gln427) in the FUCA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 40 amino acid(s) of the FUCA1 protein. This variant is present in population databases (rs118204450, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with fucosidosis (PMID: 8401503). It has also been observed to segregate with disease in related individuals. This variant is also known as Q422X. ClinVar contains an entry for this variant (Variation ID: 681). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jan 01, 1989)	no assertion criteria provided Method: literature only	FUCOSIDOSIS Affected status: not provided Allele origin: germline	OMIM Accession: SCV000020866.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 2642067 Comment on evidence: In about 20% of families with fucosidosis (230000), Southern blot analysis demonstrates that a single EcoRI restriction site in the open reading frame of the … (more) In about 20% of families with fucosidosis (230000), Southern blot analysis demonstrates that a single EcoRI restriction site in the open reading frame of the FUCA1 gene is obliterated. Kretz et al. (1989) demonstrated that the loss of the EcoRI site is determined by a C-to-T transition which results in the generation of an in-frame TAA stop codon 120-bp upstream of the normal stop codon. (less)

Comment:

Variant summary: The FUCA1 c.1279C>T (p.Gln427X) variant results in a premature termination codon, predicted to cause a truncated or absent FUCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/121354 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic FUCA1 variant (0.001118). This variant has been reported in multiple affected individuals with FUCO. In addition, the fibroblast from patients showed negligible enzyme activity and very low CRIM level for a-L-fucosidase (Seo_1993). Taken together, this variant is classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Gln427*) in the FUCA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 40 amino acid(s) of the FUCA1 protein. This variant is present in population databases (rs118204450, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with fucosidosis (PMID: 8401503). It has also been observed to segregate with disease in related individuals. This variant is also known as Q422X. ClinVar contains an entry for this variant (Variation ID: 681). For these reasons, this variant has been classified as Pathogenic.

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
Spectrum of mutations in fucosidosis.	Willems PJ	European journal of human genetics : EJHG	1999	PMID: 10094192
Fucosidosis: genetic and biochemical analysis of eight cases.	Cragg H	Journal of medical genetics	1997	PMID: 9039984
Six additional mutations in fucosidosis: three nonsense mutations and three frameshift mutations.	Seo HC	Human molecular genetics	1993	PMID: 8401503
Characterization of EcoRI mutation in fucosidosis patients: a stop codon in the open reading frame.	Kretz KA	Journal of molecular neuroscience : MN	1989	PMID: 2642067

Text-mined citations for rs118204450 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000147.5(FUCA1):c.1279C>T (p.Gln427Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs118204450 ...