ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.1720A>G (p.Ser574Gly)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002414781 SCV002716525 uncertain significance Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2023-02-13 criteria provided, single submitter clinical testing The c.1720A>G variant (also known as p.S574G), located in coding exon 15 of the NF1 gene, results from an A to G substitution at nucleotide position 1720. The serine at codon 574 is replaced by glycine, an amino acid with similar properties. This alteration has been identified in multiple individuals with a suspected or clinical diagnosis of neurofibromatosis type 1 (Lee MJ et al. Hum Mutat, 2006 Aug;27:832; Xu W et al. Int J Mol Med, 2014 Jul;34:53-60). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV003097169 SCV003441737 likely pathogenic Neurofibromatosis, type 1 2022-04-17 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 574 of the NF1 protein (p.Ser574Gly). This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product impact (PMID: 24789688). 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. This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 16835897, 24789688).

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