ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1721G>A (p.Ser574Asn) (rs1555613206)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497645 SCV000589603 likely pathogenic not provided 2017-06-14 criteria provided, single submitter clinical testing The S574N variant has been published previously in association with neurofibromatosis type 1 (Fahsold et al., 2000; Lee et al., 2006; Stewart et al., 2014). The variant has been predicted to lead to the loss of exon 15, referred to as exon 11 using alternate nomenclature; however, no functional studies were included in these publications (Fahsold et al., 2000; Stewart et al., 2014). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). S574N is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in the same residue (S574G/R) and in a nearby residue (L578R/P) have been reported in the Human Gene Mutation Database in association with neurofibromatosis type 1 (Stenson et al., 2014). In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000538065 SCV000628387 pathogenic Neurofibromatosis, type 1 2018-10-25 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 574 of the NF1 protein (p.Ser574Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. This variant also falls at the last nucleotide of exon 15 of the NF1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with neurofibromatosis type 1 (PMID: 16835897, 10712197, 24232412, Invitae). In addition, family studies have indicated that this variant was not present in the parents of an individual with neurofibromatosis, which suggests that it was de novo in that affected individual (Invitae). ClinVar contains an entry for this variant (Variation ID: 431976). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000574543 SCV000670421 likely pathogenic Hereditary cancer-predisposing syndrome 2016-03-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Last nucleotide of exon,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626735 SCV000747438 pathogenic Multiple cafe-au-lait spots 2017-01-01 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc RCV000538065 SCV000781927 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing

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