Submissions for variant NM_001042492.3(NF1):c.1370A>T (p.His457Leu)

dbSNP: rs786202763

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165738	SCV000216480	uncertain significance	Hereditary cancer-predisposing syndrome	2015-09-13	criteria provided, single submitter	clinical testing	The p.H457L variant (also known as c.1370A>T), located in coding exon 12 of the NF1 gene, results from an A to T substitution at nucleotide position 1370. The histidine at codon 457 is replaced by leucine, an amino acid with similar properties. 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 6503 samples (13006 alleles) with coverage at this position.<span style="background-color:initial">To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 110000 alleles tested) in our clinical cohort.<span style="background-color:initial"><span style="background-color:initial">This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be benign by PolyPhen<span style="background-color:initial">but deleterious by<span style="background-color:initial">SIFT in silico<span style="background-color:initial"> analyses, respectively.<span style="background-color:initial">Since supporting evidence is limited at this time, the clinical significance of<span style="background-color:initial">p.H457L<span style="background-color:initial">remains unclear.
Mendelics	RCV000709412	SCV000839132	uncertain significance	Neurofibromatosis, type 1	2018-07-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000709412	SCV000945842	likely benign	Neurofibromatosis, type 1	2025-01-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000165738	SCV002527396	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-07	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000709412	SCV002561902	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002478511	SCV002774835	uncertain significance	not provided	2024-05-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468754	SCV004190703	uncertain significance	Juvenile myelomonocytic leukemia	2023-06-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558379	SCV005047524	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-01-18	criteria provided, single submitter	clinical testing	The c.1370A>T (p.H457L) alteration is located in exon 12 (coding exon 12) of the NF1 gene. This alteration results from a A to T substitution at nucleotide position 1370, causing the histidine (H) at amino acid position 457 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV002478511	SCV005401606	uncertain significance	not provided	2024-05-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a patient with breast cancer (PMID: 35264596); This variant is associated with the following publications: (PMID: 30274822, 35264596)