Submissions for variant NM_014365.3(HSPB8):c.14A>G (p.Gln5Arg)

gnomAD frequency: 0.00009  dbSNP: rs146900850

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000687583	SCV000815159	uncertain significance	Charcot-Marie-Tooth disease axonal type 2L	2024-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 5 of the HSPB8 protein (p.Gln5Arg). This variant is present in population databases (rs146900850, gnomAD 0.02%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 567484). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000761844	SCV000892048	likely benign	not provided	2022-05-01	criteria provided, single submitter	clinical testing	HSPB8: BS1
Fulgent Genetics, Fulgent Genetics	RCV000763796	SCV000894710	uncertain significance	Charcot-Marie-Tooth disease axonal type 2L; Neuronopathy, distal hereditary motor, type 2A	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000687583	SCV001266360	uncertain significance	Charcot-Marie-Tooth disease axonal type 2L	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.
Illumina Laboratory Services, Illumina	RCV001109055	SCV001266361	likely benign	Neuronopathy, distal hereditary motor, type 2A	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000761844	SCV001470993	uncertain significance	not provided	2019-12-09	criteria provided, single submitter	clinical testing	The HSPB8 c.14A>G; p.Gln5Arg variant (rs146900850), to our knowledge, is not reported in the medical literature but is reported as uncertain significance in ClinVar (Variation ID: 567484). This variant is found in the general population with an overall allele frequency of 0.01% (31/282058 alleles) in the Genome Aggregation Database. The glutamine at codon 5 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Gln5Arg variant is uncertain at this time.
Ambry Genetics	RCV002388208	SCV002702294	likely benign	Inborn genetic diseases	2019-10-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.