ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2709G>A (p.Val903=) (rs771820789)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492711 SCV000581262 pathogenic Hereditary cancer-predisposing syndrome 2014-12-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Functionally-validated splicing mutation
Carson lab,Ohio State University Comprehensive Cancer Center RCV000415263 SCV000680081 pathogenic Neurofibromatosis, type 1 2018-02-03 no assertion criteria provided research A female patient met NIH clinical criteria for diagnosis of NF1 including a) axillary and groin freckling; b) >12 neurofibromas, of which one was verified by pathology on biopsy; c) family history of cafe au lait spots. She developed metaplastic breast cancer with somatic loss of heterozygosity of the wildtype allele at this variant position in the NF1 gene. Although this variant at c.2709[G>A] is synonymous, it has been reported previously to introduce a cryptic splice donor site, thereby resulting in deletion of downstream codons and putative changes in neurofibromin protein expression and function.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415263 SCV000492608 pathogenic Neurofibromatosis, type 1 2016-02-15 no assertion criteria provided clinical testing
Invitae RCV000415263 SCV000542048 pathogenic Neurofibromatosis, type 1 2018-09-06 criteria provided, single submitter clinical testing This sequence change affects codon 903 of the NF1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NF1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with neurofibromatosis type 1 (NF1) (PMID: 17311297, 18041031, 25074460), as well as in an individual affected with both neurofibromatosis type 1 (NF1) and breast cancer (PMID: 29449315). ClinVar contains an entry for this variant (Variation ID: 373958). Experimental studies using patient-derived RNA have shown that this silent change affects mRNA splicing and results in skipping of 144 nucleotides (r.2707_2850del144) leading to in-frame deletion of 48 amino acid residues (p.Val903_Gln950del48) from the NF1 protein (PMID: 17311297, 18041031). For these reasons, this variant has been classified as Pathogenic.

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