ClinVar Genomic variation as it relates to human health
NM_031433.4(MFRP):c.498del (p.Asn167fs)
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_031433.4(MFRP):c.498del (p.Asn167fs)
Variation ID: 4476 Accession: VCV000004476.16
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 11q23.3 11: 119345563 (GRCh38) [ NCBI UCSC ] 11: 119216273 (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 Dec 15, 2018 Feb 20, 2024 Nov 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_031433.4:c.498del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_113621.1:p.Asn167fs frameshift NM_015645.5:c.-2139del 5 prime UTR NM_031433.3:c.498delC NC_000011.10:g.119345569del NC_000011.9:g.119216279del NG_012235.1:g.6111del - Protein change
- N167fs
- Other names
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- Canonical SPDI
- NC_000011.10:119345562:GGGGGGG:GGGGGG
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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
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The frequency of the allele represented by this VCV record.
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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
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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C1QTNF5 | - | - |
GRCh38 GRCh37 |
- | 841 | |
MFRP | - | - |
GRCh38 GRCh37 |
5 | 846 |
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 (2) |
criteria provided, single submitter
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May 4, 2022 | RCV000004733.16 | |
Pathogenic (2) |
criteria provided, single submitter
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Nov 13, 2023 | RCV000161911.20 | |
Pathogenic (2) |
no assertion criteria provided
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- | RCV001579996.14 | |
MFRP-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Apr 4, 2023 | RCV004532288.1 |
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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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Nanophthalmos 2
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002517614.1
First in ClinVar: May 24, 2022 Last updated: May 24, 2022 |
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Pathogenic
(Apr 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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MFRP-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004116656.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The MFRP c.498delC variant is predicted to result in a frameshift and premature protein termination (p.Pro166Profs*26). This variant has been reported in the homozygous and … (more)
The MFRP c.498delC variant is predicted to result in a frameshift and premature protein termination (p.Pro166Profs*26). This variant has been reported in the homozygous and compound heterozygous states in individuals with nanophthalmos or retinal dystrophy (reported as 492delC in Sundin et al. 2005. PubMed ID: 15976030; Kannabiran et al. 2012. PubMed ID: 22605927; Guo et al. 2019. PubMed ID: 31266062; Prasov et al. 2020. PubMed ID: 33203948). This variant is reported in 0.042% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-119216272-TG-T). Frameshift variants in MFRP are expected to be pathogenic, and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/4476). Given the evidence, we interpret this variant as pathogenic. (less)
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Pathogenic
(Nov 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Isolated microphthalmia 5
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001411243.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Asn167Thrfs*25) in the MFRP gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Asn167Thrfs*25) in the MFRP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MFRP are known to be pathogenic (PMID: 12140190, 15976030, 20361016). This variant is present in population databases (rs587776596, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with posterior microphthalmos/nanophthalmos and retinal dystrophy in a family, and has been observed in several affected individuals (PMID: 19753314, 23112574, 23143909). It has also been observed to segregate with disease in related individuals. This variant is also known as c.492delC, p.P166fs*26, and p.P166fs*190. ClinVar contains an entry for this variant (Variation ID: 4476). 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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Pathogenic
(Jan 01, 2012)
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no assertion criteria provided
Method: literature only
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NANOPHTHALMOS 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024909.6
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Since this 1-bp deletion occurs in a stretch of 7 C nucleotides, the most 3-prime position is assigned the site of the mutation; hence this … (more)
Since this 1-bp deletion occurs in a stretch of 7 C nucleotides, the most 3-prime position is assigned the site of the mutation; hence this mutation is referred to as c.498delC rather than as c.492delC (1-BP DEL, 492C) as notated by Sundin et al. (2005). Nanophthalmos 2 In 2 sisters with nanophthalmos-2 (NNO2; 609549), Sundin et al. (2005) identified compound heterozygosity for 2 mutations in exon 5 of the MFRP gene: a 1-bp deletion (492delC) and an ile182-to-thr (I182T) substitution (606227.0004). The deletion was predicted to truncate the protein in one of the cubilin domains and remove the cysteine-rich domain. Isolated Microphthalmia 5 In 3 brothers from a consanguineous Spanish family with posterior microphthalmia, retinitis pigmentosa (RP), foveoschisis, and optic disc drusen (MCOP5; 611040), Crespi et al. (2008) identified homozygosity for a 1-bp deletion in exon 5 of the MFRP gene, which they designated 498delC, causing a frameshift predicted to result in a premature termination codon 25 codons downstream (Pro166fsTer190). The authors noted that this truncated protein would lack almost all functional domains, including the 2 cubilin-related, 2 low-density lipoprotein receptor-related, and C-terminal cysteine-rich frizzled-related domains. The deletion was present in heterozygosity in an unaffected sister. In a Mexican sister and brother with posterior microphthalmia, RP, foveoschisis, and optic disc drusen, Zenteno et al. (2009) identified compound heterozygosity for the 498delC deletion and a C-to-A transversion in exon 5 in the MFRP gene, resulting in a tyr317-to-ter (Y317X; 606227.0006) substitution. In a 42-year-old man who had high hypermetropia, retinal dysfunction with night blindness from early childhood, and optic disc drusen, Mukhopadhyay et al. (2010) identified homozygosity for the 498delC mutation in MFRP. In a 34-year-old woman with high hypermetropia and retinal dysfunction, in whom ERGs showed a rod-cone pattern of dysfunction with severe rod system involvement, Mukhopadhyay et al. (2010) identified compound heterozygosity for 498delC and a 4-bp deletion (c.1622_1625delTCTG; 606227.0007) in the MFRP gene. Both patients had foveal cystic spaces observed on optical coherence tomography. In 3 sibs from a consanguineous southern Indian family with extreme hyperopia and RP mapping to chromosome 11, Kannabiran et al. (2012) identified homozygosity for the 498delC mutation in the MFRP gene. Their unaffected parents were heterozygous for the mutation, which was not found in 100 controls. The authors noted that the affected individuals exhibited clinically atypical RP, with the 2 younger sibs having high hyperopia of +11 and +13 diopters, and the oldest sib having slightly more pigments and macular involvement. Kannabiran et al. (2012) noted that the C residue at position 498 is part of a stretch of 7 C residues, starting at c.492, that appears to represent a mutation hotspot for the MFRP gene. Ayala-Ramirez et al. (2006) reported an insertional frameshift mutation at this position (606227.0005). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809303.1 First in ClinVar: Aug 26, 2021 Last updated: Aug 26, 2021 |
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Pathogenic
(Jan 01, 2012)
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no assertion criteria provided
Method: literature only
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MICROPHTHALMIA, ISOLATED 5
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000211941.4
First in ClinVar: Mar 03, 2015 Last updated: Dec 15, 2018 |
Comment on evidence:
Since this 1-bp deletion occurs in a stretch of 7 C nucleotides, the most 3-prime position is assigned the site of the mutation; hence this … (more)
Since this 1-bp deletion occurs in a stretch of 7 C nucleotides, the most 3-prime position is assigned the site of the mutation; hence this mutation is referred to as c.498delC rather than as c.492delC (1-BP DEL, 492C) as notated by Sundin et al. (2005). Nanophthalmos 2 In 2 sisters with nanophthalmos-2 (NNO2; 609549), Sundin et al. (2005) identified compound heterozygosity for 2 mutations in exon 5 of the MFRP gene: a 1-bp deletion (492delC) and an ile182-to-thr (I182T) substitution (606227.0004). The deletion was predicted to truncate the protein in one of the cubilin domains and remove the cysteine-rich domain. Isolated Microphthalmia 5 In 3 brothers from a consanguineous Spanish family with posterior microphthalmia, retinitis pigmentosa (RP), foveoschisis, and optic disc drusen (MCOP5; 611040), Crespi et al. (2008) identified homozygosity for a 1-bp deletion in exon 5 of the MFRP gene, which they designated 498delC, causing a frameshift predicted to result in a premature termination codon 25 codons downstream (Pro166fsTer190). The authors noted that this truncated protein would lack almost all functional domains, including the 2 cubilin-related, 2 low-density lipoprotein receptor-related, and C-terminal cysteine-rich frizzled-related domains. The deletion was present in heterozygosity in an unaffected sister. In a Mexican sister and brother with posterior microphthalmia, RP, foveoschisis, and optic disc drusen, Zenteno et al. (2009) identified compound heterozygosity for the 498delC deletion and a C-to-A transversion in exon 5 in the MFRP gene, resulting in a tyr317-to-ter (Y317X; 606227.0006) substitution. In a 42-year-old man who had high hypermetropia, retinal dysfunction with night blindness from early childhood, and optic disc drusen, Mukhopadhyay et al. (2010) identified homozygosity for the 498delC mutation in MFRP. In a 34-year-old woman with high hypermetropia and retinal dysfunction, in whom ERGs showed a rod-cone pattern of dysfunction with severe rod system involvement, Mukhopadhyay et al. (2010) identified compound heterozygosity for 498delC and a 4-bp deletion (c.1622_1625delTCTG; 606227.0007) in the MFRP gene. Both patients had foveal cystic spaces observed on optical coherence tomography. In 3 sibs from a consanguineous southern Indian family with extreme hyperopia and RP mapping to chromosome 11, Kannabiran et al. (2012) identified homozygosity for the 498delC mutation in the MFRP gene. Their unaffected parents were heterozygous for the mutation, which was not found in 100 controls. The authors noted that the affected individuals exhibited clinically atypical RP, with the 2 younger sibs having high hyperopia of +11 and +13 diopters, and the oldest sib having slightly more pigments and macular involvement. Kannabiran et al. (2012) noted that the C residue at position 498 is part of a stretch of 7 C residues, starting at c.492, that appears to represent a mutation hotspot for the MFRP gene. Ayala-Ramirez et al. (2006) reported an insertional frameshift mutation at this position (606227.0005). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001959935.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 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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Coexistence of KCNV2 associated cone dystrophy with supernormal rod electroretinogram and MFRP related oculopathy in a Turkish family. | Ritter M | The British journal of ophthalmology | 2013 | PMID: 23143909 |
Membrane frizzled-related protein gene-related ophthalmological syndrome: 30-month follow-up of a sporadic case and review of genotype-phenotype correlation in the literature. | Neri A | Molecular vision | 2012 | PMID: 23112574 |
Mutations in TULP1, NR2E3, and MFRP genes in Indian families with autosomal recessive retinitis pigmentosa. | Kannabiran C | Molecular vision | 2012 | PMID: 22605927 |
A detailed phenotypic assessment of individuals affected by MFRP-related oculopathy. | Mukhopadhyay R | Molecular vision | 2010 | PMID: 20361016 |
Compound heterozygosity for a novel and a recurrent MFRP gene mutation in a family with the nanophthalmos-retinitis pigmentosa complex. | Zenteno JC | Molecular vision | 2009 | PMID: 19753314 |
A novel mutation confirms MFRP as the gene causing the syndrome of nanophthalmos-renititis pigmentosa-foveoschisis-optic disk drusen. | Crespí J | American journal of ophthalmology | 2008 | PMID: 18554571 |
A new autosomal recessive syndrome consisting of posterior microphthalmos, retinitis pigmentosa, foveoschisis, and optic disc drusen is caused by a MFRP gene mutation. | Ayala-Ramirez R | Molecular vision | 2006 | PMID: 17167404 |
Extreme hyperopia is the result of null mutations in MFRP, which encodes a Frizzled-related protein. | Sundin OH | Proceedings of the National Academy of Sciences of the United States of America | 2005 | PMID: 15976030 |
Mfrp, a gene encoding a frizzled related protein, is mutated in the mouse retinal degeneration 6. | Kameya S | Human molecular genetics | 2002 | PMID: 12140190 |
Text-mined citations for rs587776596 ...
HelpRecord last updated Jun 02, 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.