Submissions for variant NM_002506.3(NGF):c.146G>A (p.Arg49His)

gnomAD frequency: 0.00002  dbSNP: rs781072056

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000798441	SCV000938058	uncertain significance	Congenital sensory neuropathy with selective loss of small myelinated fibers	2021-08-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with histidine at codon 49 of the NGF protein (p.Arg49His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with NGF-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV000798441	SCV001257736	uncertain significance	Congenital sensory neuropathy with selective loss of small myelinated fibers	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics	RCV002388460	SCV002702196	uncertain significance	Inborn genetic diseases	2022-01-18	criteria provided, single submitter	clinical testing	The c.146G>A (p.R49H) alteration is located in exon 3 (coding exon 1) of the NGF gene. This alteration results from a G to A substitution at nucleotide position 146, causing the arginine (R) at amino acid position 49 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV000798441	SCV004050739	uncertain significance	Congenital sensory neuropathy with selective loss of small myelinated fibers	2023-04-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003884731	SCV004701031	uncertain significance	not provided	2024-01-01	criteria provided, single submitter	clinical testing	NGF: PM2, BP4
GenomeConnect, ClinGen	RCV001824886	SCV002074643	not provided	NGF-related disorder		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 04-07-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.