ClinVar Genomic variation as it relates to human health
NM_001371596.2(MFSD8):c.754+2T>A
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001371596.2(MFSD8):c.754+2T>A
Variation ID: 65897 Accession: VCV000065897.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q28.2 4: 127938781 (GRCh38) [ NCBI UCSC ] 4: 128859936 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Oct 1, 2013 Feb 14, 2024 Dec 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001371596.2:c.754+2T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001363520.3:c.553+3264T>A intron variant NM_001363521.3:c.439+4971T>A intron variant NM_001371590.2:c.619+2T>A splice donor NM_001371591.2:c.754+2T>A splice donor NM_001371592.2:c.760+2T>A splice donor NM_001371593.2:c.640+2T>A splice donor NM_001371594.2:c.607+2T>A splice donor NM_001371595.1:c.472+2T>A splice donor NM_001410765.1:c.304+4971T>A intron variant NM_001410766.1:c.640+2T>A splice donor NM_152778.4:c.754+2T>A splice donor NC_000004.12:g.127938781A>T NC_000004.11:g.128859936A>T NG_008657.1:g.32204T>A LRG_833:g.32204T>A LRG_833t1:c.754+2T>A LRG_833t2:c.754+2T>A - Protein change
- Other names
- c.754+2T>A
- Canonical SPDI
- NC_000004.12:127938780:A:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
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 | ||
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HI score
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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. |
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MFSD8 | - | - |
GRCh38 GRCh37 |
940 | 986 |
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. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 6, 2023 | RCV000056142.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 8, 2022 | RCV000188171.5 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 16, 2020 | RCV001271142.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 30, 2021 | RCV001353040.2 |
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. |
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Likely pathogenic
(Jan 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Macular dystrophy with central cone involvement
Affected status: yes
Allele origin:
unknown
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Institute of Medical Molecular Genetics, University of Zurich
Accession: SCV001548157.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Method: long-range PCR
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Pathogenic
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 7
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000447471.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The MFSD8 c.754+2T>A variant occurs in a canonical splice donor site and is therefore predicted to disrupt or distort the normal gene product. The variant … (more)
The MFSD8 c.754+2T>A variant occurs in a canonical splice donor site and is therefore predicted to disrupt or distort the normal gene product. The variant has been reported in four studies and found in a total of 12 individuals with confirmed or suspected neuronal ceroid-lipofuscinosis, including in eight individuals (including two siblings) in a homozygous state and in four individuals in a compound heterozygous state (Siintola et al. 2007; Kousi et al. 2009; Kousi et al. 2011; Craiu et al. 2015). The c.754+2T>A variant was also reported in a heterozygous state in one unaffected parent. The variant was absent from 504 control chromosomes and not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. RT-PCR showed aberrant splicing of the variant mRNA leading to an altered pattern of products including almost complete loss of the normal transcript containing exons 7-10 of the gene (Siintola et al. 2007). Based on potential impact of splice donor variants and the evidence from the literature, the c.754+2T>A variant is classified as pathogenic for neuronal ceroid-lipofuscinosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Dec 24, 2018)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 7
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368442.2
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: PVS1,PM2,PP3,PP5.
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Pathogenic
(Jul 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000241778.14
First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed … (more)
Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); A different variant affecting the same splice site (c.754+1G>A) has been reported in association with late infantile neuronal ceroid lipofuscinosis (Kousi et al., 2012); This variant is associated with the following publications: (PMID: 25525159, 19277732, 25439737, 31589614, 17564970) (less)
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Pathogenic
(Dec 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 7
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000950873.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 8 of the MFSD8 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 8 of the MFSD8 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 MFSD8 are known to be pathogenic (PMID: 19177532, 25227500, 28586915). This variant is present in population databases (rs587778809, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with MFSD8-related conditions (PMID: 17564970, 19201763, 25439737). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65897). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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pathologic
(Aug 01, 2013)
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no assertion criteria provided
Method: curation
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Neuronal Ceroid-Lipofuscinoses
Affected status: not provided
Allele origin:
not provided
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GeneReviews
Accession: SCV000087222.1
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2013 |
Comment:
Converted during submission to Pathogenic.
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Late-infantile neuronal ceroid lipofuscinosis
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001451997.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases. | Maggi J | International journal of molecular sciences | 2021 | PMID: 33546218 |
Specific Alleles of CLN7/MFSD8, a Protein That Localizes to Photoreceptor Synaptic Terminals, Cause a Spectrum of Nonsyndromic Retinal Dystrophy. | Khan KN | Investigative ophthalmology & visual science | 2017 | PMID: 28586915 |
Rett-like onset in late-infantile neuronal ceroid lipofuscinosis (CLN7) caused by compound heterozygous mutation in the MFSD8 gene and review of the literature data on clinical onset signs. | Craiu D | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2015 | PMID: 25439737 |
Mutations in MFSD8, encoding a lysosomal membrane protein, are associated with nonsyndromic autosomal recessive macular dystrophy. | Roosing S | Ophthalmology | 2015 | PMID: 25227500 |
Neuronal Ceroid-Lipofuscinoses – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2013 | PMID: 20301601 |
Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. | Kousi M | Human mutation | 2012 | PMID: 21990111 |
Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis. | Kousi M | Brain : a journal of neurology | 2009 | PMID: 19201763 |
Mutations in MFSD8/CLN7 are a frequent cause of variant-late infantile neuronal ceroid lipofuscinosis. | Aiello C | Human mutation | 2009 | PMID: 19177532 |
The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter. | Siintola E | American journal of human genetics | 2007 | PMID: 17564970 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Text-mined citations for rs587778809 ...
HelpRecord last updated Feb 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.