Submissions for variant NM_031935.3(HMCN1):c.13942G>T (p.Ala4648Ser)

dbSNP: rs367723447

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000384061	SCV000351958	uncertain significance	Age related macular degeneration 1	2018-01-12	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	RCV002519448	SCV003585206	uncertain significance	Inborn genetic diseases	2021-10-06	criteria provided, single submitter	clinical testing	The c.13942G>T (p.A4648S) alteration is located in exon 90 (coding exon 90) of the HMCN1 gene. This alteration results from a G to T substitution at nucleotide position 13942, causing the alanine (A) at amino acid position 4648 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV000384061	SCV004180595	uncertain significance	Age related macular degeneration 1	2023-04-11	criteria provided, single submitter	clinical testing
Invitae	RCV003765714	SCV004637071	uncertain significance	not provided	2022-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 4648 of the HMCN1 protein (p.Ala4648Ser). 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 294270). This variant has not been reported in the literature in individuals affected with HMCN1-related conditions. This variant is present in population databases (rs367723447, gnomAD 0.002%).