ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.862G>A (p.Val288Met) (rs755670651)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000223253 SCV000274800 uncertain significance Hereditary cancer-predisposing syndrome 2015-03-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000234015 SCV000284534 uncertain significance Neurofibromatosis, type 1 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 288 of the NF1 protein (p.Val288Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs755670651, ExAC 0.002%). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 231063). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000608961 SCV000731711 uncertain significance not specified 2017-12-14 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Val288Met var iant in NF1 has been identified by our laboratory in 1 individual with clinical features of RASopathy; however, it was inherited from an unaffected parent. This variant has also been identified in 1/111304 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs755670 651). Computational prediction tools and conservation analysis do not provide st rong support for or against an impact to the protein. In summary, while the clin ical significance of the p.Val288Met variant is uncertain, its identification in an unaffected individual suggests that it is more likely to be benign. ACMG/AMP criteria applied: BS2.

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