Submissions for variant NM_031935.3(HMCN1):c.15076C>T (p.Arg5026Trp)

gnomAD frequency: 0.00001  dbSNP: rs536701183

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001102179	SCV001258833	uncertain significance	Age related macular degeneration 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, 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.
Invitae	RCV001354700	SCV002114000	uncertain significance	not provided	2022-01-16	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 876899). This variant has not been reported in the literature in individuals affected with HMCN1-related conditions. This variant is present in population databases (rs536701183, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 5026 of the HMCN1 protein (p.Arg5026Trp).
Ambry Genetics	RCV003259094	SCV003945912	uncertain significance	Inborn genetic diseases	2023-04-25	criteria provided, single submitter	clinical testing	The c.15076C>T (p.R5026W) alteration is located in exon 97 (coding exon 97) of the HMCN1 gene. This alteration results from a C to T substitution at nucleotide position 15076, causing the arginine (R) at amino acid position 5026 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV001102179	SCV004180618	uncertain significance	Age related macular degeneration 1	2023-04-11	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354700	SCV001549381	uncertain significance	not provided		no assertion criteria provided	clinical testing	The HMCN1 p.(Arg5026Trp) variant was not identified in the literature nor was it identified in the ClinVar, COGR, MutDB, or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs536701183) and in Cosmic, as a somatic mutation in prostate tumour tissue. The variant was identified in control databases in 10 of 282622 chromosomes at a frequency of 0.000035 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 7218 chromosomes (freq: 0.000277), South Asian in 4 of 30616 chromosomes (freq: 0.000131), East Asian in 2 of 19930 chromosomes (freq: 0.0001) and European (non-Finnish) in 2 of 128980 chromosomes (freq: 0.000016); it was not observed in the African, Latino, Ashkenazi Jewish, and European (Finnish) populations. The p.Arg5026 residue is highly conserved in mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Arg5026 variant may impact the protein. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.