Submissions for variant NM_001042492.3(NF1):c.2764G>A (p.Gly922Ser)

dbSNP: rs1135402831

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000497105	SCV001478609	likely pathogenic	Neurofibromatosis, type 1	2021-01-28	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.2764G>A (p.Gly922Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic exonic 5' splice donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Ars_2003). The variant was absent in 251090 control chromosomes. c.2764G>A has been reported in the literature in at-least two individuals affected with some but not all diagnostic features of Neurofibromatosis Type 1 as well as in at-least one individual with a suspected diagnosis of Neurofibromatosis type 1 and also subsequently cited by others (example, Ars_2003, Pros_2008, Anastaski_2017, Bonatti_2017, Yoshida_2018). These data indicate that the variant may be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evalution and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000497105	SCV001586754	pathogenic	Neurofibromatosis, type 1	2020-08-04	criteria provided, single submitter	clinical testing	Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 10607834). For these reasons, this variant has been classified as Pathogenic. 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. This variant has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10607834, 28961165). ClinVar contains an entry for this variant (Variation ID: 431608). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 922 of the NF1 protein (p.Gly922Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine.
Genome-Nilou Lab	RCV000497105	SCV002561801	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Medical Genetics, University of Parma	RCV000497105	SCV000588747	uncertain significance	Neurofibromatosis, type 1	2017-02-02	no assertion criteria provided	clinical testing