Submissions for variant NM_001042492.3(NF1):c.107C>G (p.Thr36Ser)

gnomAD frequency: 0.00015  dbSNP: rs199966218

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129384	SCV000184150	uncertain significance	Hereditary cancer-predisposing syndrome	2016-02-10	criteria provided, single submitter	clinical testing	The p.T36S variant (also known as c.107C>G), located in coding exon 2 of the NF1 gene, results from a C to G substitution at nucleotide position 107. The threonine at codon 36 is replaced by serine, an amino acid with similar properties. This variant was previously reported in two members of one Chinese Han family affected with NF1, but not detected in one unaffected member of same family, or in 110 healthy controls (Cai Y et al. J. Dermatol. Sci. 2005; 39:125-7). This variant was previously reported in the SNPDatabase as rs199966218. Based on data from the 1000 Genomes Project, the G allele has an overall frequency of approximately 0.05% (1/2098) total alleles studied. The highest observed frequency was 0.54% (1/186) Finnish alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the G allele has an overall frequency of approximately 0.03% (4/13006) total alleles studied and 0.05% (4/8600) European American alleles. To date, this alteration has been detected with an allele frequency of approximately 0.017% (greater than 110000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of p.T36S remains unclear.​
Invitae	RCV000196537	SCV000253198	likely benign	Neurofibromatosis, type 1	2024-01-28	criteria provided, single submitter	clinical testing
Medical Genetics, University of Parma	RCV000196537	SCV000588693	benign	Neurofibromatosis, type 1	2022-08-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000680810	SCV000808255	likely benign	not provided	2021-02-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24803665, 16005615)
CeGaT Center for Human Genetics Tuebingen	RCV000680810	SCV002498261	likely benign	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129384	SCV002527373	likely benign	Hereditary cancer-predisposing syndrome	2021-04-27	criteria provided, single submitter	curation
Ambry Genetics	RCV002415623	SCV002725910	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2018-05-31	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV000680810	SCV003815865	uncertain significance	not provided	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398757	SCV004121947	likely benign	not specified	2023-10-20	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.107C>G (p.Thr36Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 251066 control chromosomes. The observed variant frequency is approximately 1.32 fold of the estimated maximal expected allele frequency for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 phenotype (0.00021), strongly suggesting that the variant is benign. c.107C>G has been reported in the literature in individuals from one family affected with Neurofibromatosis Type 1 (e.g. Cai_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16005615, 27848944). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=2), likely benign (n=5), benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000129384	SCV004228144	benign	Hereditary cancer-predisposing syndrome	2023-10-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551242	SCV004755678	likely benign	NF1-related disorder	2022-03-04	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000680810	SCV001807253	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000680810	SCV001965080	likely benign	not provided		no assertion criteria provided	clinical testing