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NM_020366.4(RPGRIP1):c.3793_3794insGAAA (p.Val1265fs) AND Leber congenital amaurosis 6

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Dec 3, 2018
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001005015.2

Allele description [Variation Report for NM_020366.4(RPGRIP1):c.3793_3794insGAAA (p.Val1265fs)]

NM_020366.4(RPGRIP1):c.3793_3794insGAAA (p.Val1265fs)

Gene:
RPGRIP1:RPGR interacting protein 1 [Gene - OMIM - HGNC]
Variant type:
Insertion
Cytogenetic location:
14q11.2
Genomic location:
Preferred name:
NM_020366.4(RPGRIP1):c.3793_3794insGAAA (p.Val1265fs)
HGVS:
  • NC_000014.9:g.21351148_21351149insGAAA
  • NG_008933.1:g.68172_68173insGAAA
  • NG_009932.1:g.38118_38119insTTTC
  • NM_001377523.1:c.1771_1772insGAAA
  • NM_001377948.1:c.2719_2720insGAAA
  • NM_001377949.1:c.1879_1880insGAAA
  • NM_001377950.1:c.1771_1772insGAAA
  • NM_001377951.1:c.1276_1277insGAAA
  • NM_020366.4:c.3793_3794insGAAAMANE SELECT
  • NP_001364452.1:p.Val591fs
  • NP_001364877.1:p.Val907fs
  • NP_001364878.1:p.Val627fs
  • NP_001364879.1:p.Val591fs
  • NP_001364880.1:p.Val426fs
  • NP_065099.3:p.Val1265fs
  • NC_000014.8:g.21819307_21819308insGAAA
  • NC_000014.8:g.21819307_21819308insGAAA
  • p.Val1265GlyfsTer19
Protein change:
V1265fs
Links:
dbSNP: rs1468976582
NCBI 1000 Genomes Browser:
rs1468976582
Molecular consequence:
  • NM_001377523.1:c.1771_1772insGAAA - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001377948.1:c.2719_2720insGAAA - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001377949.1:c.1879_1880insGAAA - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001377950.1:c.1771_1772insGAAA - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001377951.1:c.1276_1277insGAAA - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_020366.4:c.3793_3794insGAAA - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:
Leber congenital amaurosis 6 (LCA6)
Identifiers:
MONDO: MONDO:0013446; MedGen: C1854260; Orphanet: 65; OMIM: 613826

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001164577Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Dec 3, 2018) 		germlineresearch

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedresearch

Citations

PubMed

Contribution of noncoding pathogenic variants to RPGRIP1-mediated inherited retinal degeneration.

Jamshidi F, Place EM, Mehrotra S, Navarro-Gomez D, Maher M, Branham KE, Valkanas E, Cherry TJ, Lek M, MacArthur D, Pierce EA, Bujakowska KM.

Genet Med. 2019 Mar;21(3):694-704. doi: 10.1038/s41436-018-0104-7. Epub 2018 Aug 3.

PubMed [citation]
PMID:
30072743
PMCID:
PMC6399075

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001164577.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (2)

Description

The heterozygous p.Val1265GlyfsTer19 variant in RPGRIP1 was identified by our study in the compound heterozygous state with an exon duplication in the same gene in one individual with Leber congenital amaurosis (PMID: 30072743). The presence of this variant in combination with an exon duplication variant and in an individual with Leber congenital amaurosis increases the likelihood that the p.Val1265GlyfsTer19 variant is pathogenic. The p.Val1265GlyfsTer19 variant in RPGRIP1 has not been previously reported in individuals with Leber congenital amaurosis but has been identified in 0.0009014% (1/110936) of European (non-Finnish) chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, the frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 1265 and leads to a premature termination codon 19 amino acids downstream. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Greater than 10% of pathogenic variants reported in association with Leber Congenital Amaurosis in ClinVar are loss of function variants, including at least three pathogenic loss of function variants across multiple exons. Loss of function of the RPGRIP1 gene is an established disease mechanism in autosomal recessive Leber Congenital Amarosis. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PVS1_Moderate, PM3_Supporting (Richards 2015).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 30, 2024