Submissions for variant NM_001042492.3(NF1):c.1721G>A (p.Ser574Asn)

dbSNP: rs1555613206

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497645	SCV000589603	pathogenic	not provided	2023-07-04	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 10712197, 16835897, 24232412, 29673180, 29685074, 25486365, 30014477)
Invitae	RCV000538065	SCV000628387	pathogenic	Neurofibromatosis, type 1	2022-08-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. ClinVar contains an entry for this variant (Variation ID: 431976). This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10712197, 16835897, 24232412; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 574 of the NF1 protein (p.Ser574Asn). This variant also falls at the last nucleotide of exon 15, which is part of the consensus splice site for this exon.
Ambry Genetics	RCV000574543	SCV000670421	likely pathogenic	Hereditary cancer-predisposing syndrome	2016-03-03	criteria provided, single submitter	clinical testing	The c.1721G>A variant (also known as p.S574N), located in coding exon 15 of the NF1 gene, results from a G to A substitution at nucleotide position 1721. The amino acid change results in serine to asparagine at codon 574, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 15, which makes it likely to have some effect on normal mRNA splicing. <span style="font-family:sans-serif,arial,verdana,trebuchet ms">This mutationhas been previously reported in multiple individuals diagnosedwithneurofibromatosistype1 (FahsoldR et al,Am. J. Hum. Genet. 2000 Mar; 66(3):790-818;Lee MJ et al,Hum.Mutat. 2006 Aug; 27(8):832)<span style="font-family:sans-serif,arial,verdana,trebuchet ms">.This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6500 samples (13000 alleles) with coverage at this position. Both the nucleotide andamino acid positions are highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. In addition, this alteration is predicted to be tolerated by in silico analysis.Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626735	SCV000747438	pathogenic	Cafe au lait spots, multiple	2017-01-01	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000538065	SCV000781927	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000538065	SCV002561693	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002404301	SCV002713643	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-06-03	criteria provided, single submitter	clinical testing	The c.1721G>A pathogenic mutation (also known as p.S574N), located in coding exon 15 of the NF1 gene, results from a G to A substitution at nucleotide position 1721. The amino acid change results in serine to asparagine at codon 574, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 15, which makes it likely to have some effect on normal mRNA splicing. This alteration has been previously reported in multiple individuals diagnosed with neurofibromatosis type 1 (Fahsold R et al, Am. J. Hum. Genet. 2000 Mar; 66(3):790-818; Lee MJ et al, Hum. Mutat. 2006 Aug; 27(8):832; Palma Milla C et al. Ann. Hum. Genet. 2018 Nov;82(6):425-436; Stella A et al. Genes (Basel) 2018 Apr;9(4)). This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is unavailable. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.