Submissions for variant NM_001042492.3(NF1):c.128T>C (p.Leu43Pro)

dbSNP: rs1555604899

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000542948	SCV000628359	pathogenic	Neurofibromatosis, type 1	2022-03-07	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 457527). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 43 of the NF1 protein (p.Leu43Pro). 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: 28529006, 31370276; Invitae). In at least one individual the variant was observed to be de novo. 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. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000681046	SCV000808499	likely pathogenic	not provided	2021-07-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); 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: 31370276, 28529006)
Ambry Genetics	RCV002316488	SCV001171022	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-03-28	criteria provided, single submitter	clinical testing	The p.L43P variant (also known as c.128T>C), located in coding exon 2 of the NF1 gene, results from a T to C substitution at nucleotide position 128. The leucine at codon 43 is replaced by proline, an amino acid with similar properties. This alteration has been reported in individuals with NF1-associated features (Paulo P et al. J Mol Diagn. 2017 07;19:502-513; Giugliano T et al. Genes (Basel). 2019 Jul;10:; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
MVZ Dr. Eberhard & Partner Dortmund	RCV000542948	SCV001478889	pathogenic	Neurofibromatosis, type 1	2020-11-06	criteria provided, single submitter	clinical testing	This transition at a highly conserved position (phyloP: 4.56 [-14.1;6.4]) is likely to cause an amino acid change from Leu43 to Pro. This amino acid is highly conserved up to Baker´s yeast (considering 12 species) and multiple lines of computational evidence support a deleterious effect on the gene or gene product (SIFT (v6.2.0: deliterious (score 0, median 3.39; MutationTaster (v2013): disease causing (prob 1); Polyphen: probably pathogenic). There is also a moderate physicochemical difference between Leu and Pro (Grantham distance: 98 [0-215]). This variant is absent from controls in Exome Sequencing Project, 1000 Genomes Project and Exome Aggregation Consortium. This variant was reported as pathogenic in LOVD.
Genome-Nilou Lab	RCV000542948	SCV002561550	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000542948	SCV005382504	likely pathogenic	Neurofibromatosis, type 1	2023-05-20	criteria provided, single submitter	clinical testing	The missense c.128T>C (p.Leu43Pro) variant in the NF1 gene has been observed in individual(s) with neurofibromatosis type 1 (Giugliano, Teresa et al.,2019). A different amino acid change (p.Leu43Gln) has been submitted to clinvar as Likely Pathogenic. The variant is absent in gnomAD Exomes. It is submitted to ClinVar as Pathogenic/Likely Pathogenic. The amino acid Leucine at position 43 is changed to a Proline changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT – Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid proline in NF1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Functional studies are required to prove the pathoegnicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic.