ClinVar Genomic variation as it relates to human health
NM_001371596.2(MFSD8):c.416G>A (p.Arg139His)
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.
Pathogenic(1); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001371596.2(MFSD8):c.416G>A (p.Arg139His)
Variation ID: 431131 Accession: VCV000431131.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q28.2 4: 127943775 (GRCh38) [ NCBI UCSC ] 4: 128864930 (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 Aug 5, 2017 Feb 7, 2023 Jul 6, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001371596.2:c.416G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001358525.1:p.Arg139His missense NM_001363520.3:c.416G>A NP_001350449.1:p.Arg139His missense NM_001363521.3:c.416G>A NP_001350450.1:p.Arg139His missense NM_001371590.2:c.281G>A NP_001358519.1:p.Arg94His missense NM_001371591.2:c.416G>A NP_001358520.1:p.Arg139His missense NM_001371592.2:c.416G>A NP_001358521.1:p.Arg139His missense NM_001371593.2:c.416G>A NP_001358522.1:p.Arg139His missense NM_001371594.2:c.416G>A NP_001358523.1:p.Arg139His missense NM_001371595.1:c.281G>A NP_001358524.1:p.Arg94His missense NM_001410765.1:c.281G>A NP_001397694.1:p.Arg94His missense NM_001410766.1:c.416G>A NP_001397695.1:p.Arg139His missense NM_152778.4:c.416G>A NP_689991.1:p.Arg139His missense NC_000004.12:g.127943775C>T NC_000004.11:g.128864930C>T NG_008657.1:g.27210G>A LRG_833:g.27210G>A LRG_833t1:c.416G>A LRG_833p1:p.Arg139His LRG_833t2:c.416G>A LRG_833p2:p.Arg139His - Protein change
- R139H, R94H
- Other names
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- Canonical SPDI
- NC_000004.12:127943774:C: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.
The Genome Aggregation Database (gnomAD) 0.00001
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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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 |
950 | 996 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jul 6, 2022 | RCV000496155.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 10, 2022 | RCV002222533.2 |
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
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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
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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
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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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Pathogenic
(Jan 06, 2017)
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criteria provided, single submitter
Method: clinical testing
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Ceroid lipofuscinosis, neuronal, 7
Affected status: yes
Allele origin:
paternal
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Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris
Accession: SCV000586766.1
First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017 |
Comment:
peripheric neuropathy; global cerebral atrophy; epilepsy (myoclonia); severe regression of acquisitions starting at 3 years old
Number of individuals with the variant: 1
Age: 0-9 years
Sex: male
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Likely pathogenic
(Mar 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002500311.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
Variant summary: MFSD8 c.416G>A (p.Arg139His) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. … (more)
Variant summary: MFSD8 c.416G>A (p.Arg139His) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251244 control chromosomes (gnomAD). c.416G>A has been reported in the literature in homozygous and compound heterozygous individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (examples: Kousi_2009, Cherot_2017, Jilani_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 7
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002820226.1
First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023 |
Comment:
The MFSD8 c.416G>A(p.Arg139His) variant has been reported in homozygous state in individuals affected with neuronal ceroid lipofuscinoses (NCLs) (Kousi, Maria, et al). This variant is … (more)
The MFSD8 c.416G>A(p.Arg139His) variant has been reported in homozygous state in individuals affected with neuronal ceroid lipofuscinoses (NCLs) (Kousi, Maria, et al). This variant is reported with the allele frequency (0.0003980%) in the gnomad and novel in 1000 genome database. It has been submitted to ClinVar as Pathogenic. The amino acid Arg at position 139 is changed to a His changing protein sequence and it might alter its composition and physicochemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg139His in MFSD8 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Global developmental delay (present) , Motor regression (present) , Frequent falls (present) , Delayed speech and language development (present) , Myoclonus (present) , Deeply set … (more)
Global developmental delay (present) , Motor regression (present) , Frequent falls (present) , Delayed speech and language development (present) , Myoclonus (present) , Deeply set eye (present) (less)
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Uncertain significance
(Jul 06, 2022)
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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: SCV002193184.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 139 of the MFSD8 protein (p.Arg139His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 139 of the MFSD8 protein (p.Arg139His). This variant is present in population databases (rs749704755, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of MFSD8-related conditions (PMID: 19201763, 28708303). ClinVar contains an entry for this variant (Variation ID: 431131). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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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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High diagnostic yield of direct Sanger sequencing in the diagnosis of neuronal ceroid lipofuscinoses. | Jilani A | JIMD reports | 2019 | PMID: 31741823 |
Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients. | Chérot E | Clinical genetics | 2018 | PMID: 28708303 |
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 |
Text-mined citations for rs749704755 ...
HelpRecord last updated Apr 06, 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.