The c.863+1G>A variant in MFSD8 has not been previously reported in individuals with late-infantile neuronal ceroid lipofuscinosis and was absent from large pop ulation studies. This variant occurs in the invariant region (+/- 1,2) of the sp lice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, this variant meets our criteria to be c lassified as pathogenic for late-infantile neuronal ceroid lipofuscinosis in an autosomal recessive manner.
ClinVar Genomic variation as it relates to human health
NM_001371596.2(MFSD8):c.863+1G>A
Germline
Classification
Help
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.
(10)
Help
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
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001371596.2(MFSD8):c.863+1G>A
Variation ID: 504888 Accession: VCV000504888.21
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 4q28.2 4: 127932984 (GRCh38) [ NCBI UCSC ] 4: 128854139 (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 9, 2018 Oct 26, 2024 Aug 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001371596.2:c.863+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001363520.3:c.662+1G>A splice donor NM_001363521.3:c.548+1G>A splice donor NM_001371590.2:c.728+1G>A splice donor NM_001371591.2:c.863+1G>A splice donor NM_001371592.2:c.869+1G>A splice donor NM_001371593.2:c.749+1G>A splice donor NM_001371594.2:c.716+1G>A splice donor NM_001371595.1:c.581+1G>A splice donor NM_001410765.1:c.413+1G>A splice donor NM_001410766.1:c.749+1G>A splice donor NM_152778.4:c.863+1G>A splice donor NC_000004.12:g.127932984C>T NC_000004.11:g.128854139C>T NG_008657.1:g.38001G>A LRG_833:g.38001G>A LRG_833t1:c.863+1G>A LRG_833t2:c.863+1G>A - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000004.12:127932983:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
sequence_variant_affecting_splicing; Sequence Ontology [ SO:1000071]
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| MFSD8 | - | - |
GRCh38 GRCh37 |
951 | 997 | |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, single submitter
|
Feb 19, 2016 | RCV000616705.6 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2024 | RCV001067482.13 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 16, 2023 | RCV001783107.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 12, 2022 | RCV002529305.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Feb 19, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
None
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711766.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The c.863+1G>A variant in MFSD8 has not been previously reported in individuals with late-infantile neuronal ceroid lipofuscinosis and was absent from large pop ulation studies. … (more)
The c.863+1G>A variant in MFSD8 has not been previously reported in individuals with late-infantile neuronal ceroid lipofuscinosis and was absent from large pop ulation studies. This variant occurs in the invariant region (+/- 1,2) of the sp lice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, this variant meets our criteria to be c lassified as pathogenic for late-infantile neuronal ceroid lipofuscinosis in an autosomal recessive manner. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Oct 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 7
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002581237.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PM3, PM6, PM2_SUP
|
Number of individuals with the variant: 1
Sex: male
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 7
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047740.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The MFSD8 c.863+1G>A variant has been reported in individuals affected with Ceroid lipofuscinosis, neuronal, 7 (Monies et. al., 2017; Aiello et.al., 2009). The c.863+1G>A variant … (more)
The MFSD8 c.863+1G>A variant has been reported in individuals affected with Ceroid lipofuscinosis, neuronal, 7 (Monies et. al., 2017; Aiello et.al., 2009). The c.863+1G>A variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.0004% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (Baralle D, Baralle M., 2005) and loss-of-function variants in MFSD8 are known to be pathogenic (Aiello et.al., 2009). For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Seizure (present)
|
|
|
Pathogenic
(Dec 31, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024352.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Neuronal ceroid lipofuscinosis 7
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001232548.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 9 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 9 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 (rs200319160, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with MFSD8-related conditions (PMID: 19177532, 28600779). ClinVar contains an entry for this variant (Variation ID: 504888). 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)
|
|
|
Pathogenic
(Mar 17, 2024)
|
criteria provided, single submitter
Method: research
|
Neuronal ceroid lipofuscinosis 7
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004805015.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
|
|
|
Pathogenic
(Aug 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003742948.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.863+1G>A intronic alteration consists of a G to A substitution one nucleotide after exon 9 (coding exon 8) of the MFSD8 gene. Alterations that … (more)
The c.863+1G>A intronic alteration consists of a G to A substitution one nucleotide after exon 9 (coding exon 8) of the MFSD8 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of <0.001% (1/251090) total alleles studied. The highest observed frequency was 0.005% (1/18394) of East Asian alleles. This alteration has been reported in the homozygous state in individuals with features consistent with MFSD8-related neuronal ceroid lipofuscinosis (Aiello, 2009; Monies, 2017). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
|
Pathogenic
(May 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005326278.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
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; … (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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 19177532, 36034292, 33333116, 30609409, 28600779) (less)
|
|
|
Pathogenic
(Aug 01, 2024)
|
criteria provided, single submitter
Method: clinical testing, in vitro
|
Neuronal ceroid lipofuscinosis 7
(Autosomal recessive inheritance)
Affected status: yes, not applicable
Allele origin:
inherited,
not applicable
|
De Paul lab, Instituto de Investigacion En Ciencias de La Salud , Consejo Nacional de Investigaciones Cientificas y Tecnicas
Accession: SCV005375340.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Periventricular white matter hyperintensities (present) , Cerebellar atrophy (present) , EEG abnormality (present) , Retinitis pigmentosa inversa (present) , Optic disc pallor (present) , Undetectable … (more)
Periventricular white matter hyperintensities (present) , Cerebellar atrophy (present) , EEG abnormality (present) , Retinitis pigmentosa inversa (present) , Optic disc pallor (present) , Undetectable visual evoked potentials (present) , Generalized myoclonic seizure (present) , Atypical absence seizure (present) , Myoclonus (present) , Hyperreflexia (present) (less)
Age: 4-5 years
Sex: male
Ethnicity/Population group: Hispanic
Geographic origin: Argentina
Method: NCL genes panel sequencing
Observation 2:
Method: Minigen reporter assay
Result:
Minigen reporter assay shows an altered splicing mechanism.
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Late-infantile neuronal ceroid lipofuscinosis
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001451996.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
Comment:
Comment:
The MFSD8 c.863+1G>A variant has been reported in individuals affected with Ceroid lipofuscinosis, neuronal, 7 (Monies et. al., 2017; Aiello et.al., 2009). The c.863+1G>A variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.0004% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (Baralle D, Baralle M., 2005) and loss-of-function variants in MFSD8 are known to be pathogenic (Aiello et.al., 2009). For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change affects a donor splice site in intron 9 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 (rs200319160, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with MFSD8-related conditions (PMID: 19177532, 28600779). ClinVar contains an entry for this variant (Variation ID: 504888). 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.
Comment:
The c.863+1G>A intronic alteration consists of a G to A substitution one nucleotide after exon 9 (coding exon 8) of the MFSD8 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of <0.001% (1/251090) total alleles studied. The highest observed frequency was 0.005% (1/18394) of East Asian alleles. This alteration has been reported in the homozygous state in individuals with features consistent with MFSD8-related neuronal ceroid lipofuscinosis (Aiello, 2009; Monies, 2017). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.
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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 19177532, 36034292, 33333116, 30609409, 28600779)
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. |
|---|---|---|---|---|
|
sequence_variant_affecting_splicing
|
Method citation(s):
|
|
De Paul lab, Instituto de Investigacion En Ciencias de La Salud , Consejo Nacional de Investigaciones Cientificas y Tecnicas
Accession: SCV005375340.1
|
|
Comment:
The c.863+1G>A variant in MFSD8 has not been previously reported in individuals with late-infantile neuronal ceroid lipofuscinosis and was absent from large pop ulation studies. This variant occurs in the invariant region (+/- 1,2) of the sp lice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, this variant meets our criteria to be c lassified as pathogenic for late-infantile neuronal ceroid lipofuscinosis in an autosomal recessive manner.
Comment:
The MFSD8 c.863+1G>A variant has been reported in individuals affected with Ceroid lipofuscinosis, neuronal, 7 (Monies et. al., 2017; Aiello et.al., 2009). The c.863+1G>A variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.0004% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (Baralle D, Baralle M., 2005) and loss-of-function variants in MFSD8 are known to be pathogenic (Aiello et.al., 2009). For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change affects a donor splice site in intron 9 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 (rs200319160, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with MFSD8-related conditions (PMID: 19177532, 28600779). ClinVar contains an entry for this variant (Variation ID: 504888). 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.
Comment:
The c.863+1G>A intronic alteration consists of a G to A substitution one nucleotide after exon 9 (coding exon 8) of the MFSD8 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of <0.001% (1/251090) total alleles studied. The highest observed frequency was 0.005% (1/18394) of East Asian alleles. This alteration has been reported in the homozygous state in individuals with features consistent with MFSD8-related neuronal ceroid lipofuscinosis (Aiello, 2009; Monies, 2017). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.
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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 19177532, 36034292, 33333116, 30609409, 28600779)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes. | Monies D | Human genetics | 2017 | PMID: 28600779 |
| 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 |
| Mutations in MFSD8, encoding a lysosomal membrane protein, are associated with nonsyndromic autosomal recessive macular dystrophy. | Roosing S | Ophthalmology | 2015 | PMID: 25227500 |
| Mutations in MFSD8/CLN7 are a frequent cause of variant-late infantile neuronal ceroid lipofuscinosis. | Aiello C | Human mutation | 2009 | PMID: 19177532 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Text-mined citations for rs200319160 ...
HelpThese 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 27, 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.