Submissions for variant NM_001540.5(HSPB1):c.364+6C>G

dbSNP: rs753061670

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000518370	SCV000613672	uncertain significance	not specified	2016-09-29	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727252	SCV000706978	uncertain significance	not provided	2017-04-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001051779	SCV001215956	uncertain significance	Charcot-Marie-Tooth disease axonal type 2F	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change falls in intron 1 of the HSPB1 gene. It does not directly change the encoded amino acid sequence of the HSPB1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs753061670, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with HSPB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 447529). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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	RCV001162476	SCV001324430	uncertain significance	Neuronopathy, distal hereditary motor, type 2B	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.
Illumina Laboratory Services, Illumina	RCV001051779	SCV001324431	uncertain significance	Charcot-Marie-Tooth disease axonal type 2F	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.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001172559	SCV001335621	likely benign	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002455992	SCV002617830	likely benign	Inborn genetic diseases	2022-09-02	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.