Submissions for variant NM_001042492.3(NF1):c.1062G>A (p.Lys354=)

dbSNP: rs1131691118

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002311242	SCV000581327	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2016-06-06	criteria provided, single submitter	clinical testing	The c.1062G>A variant (also known as p.K354K), located in coding exon 9 of the NF1 gene, results from a G to A substitution at nucleotide position 1062. This nucleotide substitution does not change the lysine at codon 354. However, this change occurs in the last base pair of coding exon 9, which makes it likely to have some effect on normal mRNA splicing. This variant was shown to have an effect on splicing at the mRNA level resulting in the in-frame skipping of exon 9. In addition, this variant was found in one individual who met diagnostic criteria and another individual whose phenotype was clinically suspicious for neurofibromatosis type 1 (Fahsold et al., Am. J. Hum. Genet. 2000 Mar; 66(3):790-818; Pros et al., Hum. Mutat. 2008 Sep; 29(9):E173-93). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001386163	SCV001586296	pathogenic	Neurofibromatosis, type 1	2023-09-08	criteria provided, single submitter	clinical testing	This sequence change affects codon 354 of the NF1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NF1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10712197, 29673180). ClinVar contains an entry for this variant (Variation ID: 428998). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of 9, but is expected to preserve the integrity of the reading-frame (PMID: 10712197, 18546366). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV001386163	SCV002561624	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
3billion	RCV001386163	SCV002573220	likely pathogenic	Neurofibromatosis, type 1	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 18546366). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.82). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000428998). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
MGZ Medical Genetics Center	RCV001386163	SCV002581858	likely pathogenic	Neurofibromatosis, type 1	2022-08-25	criteria provided, single submitter	clinical testing
GeneDx	RCV003159594	SCV003915014	likely pathogenic	not provided	2022-10-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Observed in patients with NF1-related clinical features (Fahsold et al., 2000; Pros et al., 2008); Located at the last nucleotide of the exon, and demonstrated to result in abnormal splicing leading to an in-frame deletion of the adjacent exon (Fahsold et al., 2000; Smith et al., 2006; Pros et al., 2008); This variant is associated with the following publications: (PMID: 25525159, 16825284, 10712197, 18546366, 29673180, 9536098, 11967553, 17576681)
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001386163	SCV005088700	likely pathogenic	Neurofibromatosis, type 1	2024-07-30	criteria provided, single submitter	clinical testing