Submissions for variant NM_001042492.3(NF1):c.989C>T (p.Ala330Val)

dbSNP: rs1555610898

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659974	SCV000781889	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000680813	SCV000808259	pathogenic	not provided	2021-05-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: exonic splice variant demonstrated to result in loss of last 25 amino acids of exon 9, also reported as exon 7 (Wimmer 2007, Sabbagh 2013); Not observed in large population cohorts (Lek 2016); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17311297, 23913538, 23758643, 23906300, 31776437)
Invitae	RCV000659974	SCV000938737	pathogenic	Neurofibromatosis, type 1	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 330 of the NF1 protein (p.Ala330Val). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 25 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 17311297, 23758643, 23913538, 31776437; Invitae). ClinVar contains an entry for this variant (Variation ID: 547578). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function. Studies have shown that this missense change results in the activation of a cryptic splice site in exon 9 (PMID: 23758643). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000659974	SCV002561617	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002386131	SCV002690968	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-06-29	criteria provided, single submitter	clinical testing	The p.A330V variant (also known as c.989C>T), located in coding exon 9 of the NF1 gene, results from a C to T substitution at nucleotide position 989. The alanine at codon 330 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species and this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with neurofibromatosis type 1 (Wimmer K. et al, Hum Mutat. 2007 Jun;28(6):599-612; Bolcekova A. et al, Neoplasma 2013 ;60(6):655-65; Sabbagh A. et al, Hum Mutat. 2013 Nov;34(11):1510-8; Kang E et al, J Hum Genet. 2020 Jan;65(2):79-89). Additionally, functional studies have reported that this alteration results in abnormal splicing (Nemethova M. et al, Ann Hum Genet. 2013 Sep;77(5):364-79). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.