Submissions for variant NM_001042492.3(NF1):c.4929G>A (p.Val1643=)

gnomAD frequency: 0.01527  dbSNP: rs17880521

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163317	SCV000213845	benign	Hereditary cancer-predisposing syndrome	2014-11-21	criteria provided, single submitter	clinical testing	General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000215429	SCV000269456	benign	not specified	2014-11-20	criteria provided, single submitter	clinical testing	p.Val1643Val in exon 37 of NF1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 0.2% (21/8600) of Eu ropean American chromosomes and 4.3% (191/4406) of African American chromosomes by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/; dbSNP rs17880521).
PreventionGenetics, part of Exact Sciences	RCV000215429	SCV000306273	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000293980	SCV000401761	benign	Café-au-lait macules with pulmonary stenosis	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000348881	SCV000401762	benign	Neurofibromatosis-Noonan syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000396178	SCV000401763	benign	Neurofibromatosis, type 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000309383	SCV000401764	benign	Neurofibromatosis, familial spinal	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000587787	SCV000521675	benign	not provided	2016-06-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000396178	SCV000554968	benign	Neurofibromatosis, type 1	2025-02-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587787	SCV000604480	benign	not provided	2023-11-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587787	SCV000696397	benign	not provided	2016-08-30	criteria provided, single submitter	clinical testing	Variant summary: The NF1 c.4866G>A (p.Val1622Val) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 3/5 splice prediction tools predict no significant impact on splicing. ESE finder predicts that this variant may affect ESE site of SC35. This variant was found in 687/121388 control chromosomes (11 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0441346 (459/10400). This frequency is about 212 times the estimated maximal expected allele frequency of a pathogenic NF1 variant (0.0002084), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. This variant has been reported in NF1 patients and RT-PCR showed no changes on transcripts; authors classified this variant as a polymorphism (Boulandet, 2000). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000396178	SCV001479290	benign	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163317	SCV002527595	benign	Hereditary cancer-predisposing syndrome	2020-03-23	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000396178	SCV002560785	benign	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336380	SCV002639409	benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2015-03-21	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
CeGaT Center for Human Genetics Tuebingen	RCV000587787	SCV003917912	benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	NF1: BP4, BP7, BS1, BS2
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000309383	SCV004016410	benign	Neurofibromatosis, familial spinal	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000587787	SCV005253784	benign	not provided		criteria provided, single submitter	not provided
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000215429	SCV001808533	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000215429	SCV001967116	benign	not specified		no assertion criteria provided	clinical testing