Submissions for variant NM_001540.5(HSPB1):c.80G>C (p.Arg27Pro)

gnomAD frequency: 0.00019  dbSNP: rs367662394

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000416180	SCV000292582	uncertain significance	not provided	2017-06-22	criteria provided, single submitter	clinical testing	The R27P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, nor with any significant frequency in the 1000 Genomes Project. The R27P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant
CeGaT Center for Human Genetics Tuebingen	RCV000416180	SCV000493283	uncertain significance	not provided	2016-05-01	criteria provided, single submitter	clinical testing
Invitae	RCV001086814	SCV000561799	likely benign	Charcot-Marie-Tooth disease axonal type 2F	2023-10-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000416180	SCV000885571	uncertain significance	not provided	2018-03-09	criteria provided, single submitter	clinical testing	The p.Arg27Pro variant (rs367662394) variant was reported in one patient in a CMT cohort referred to for genetic testing (DiVincenzo 2014). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.06 percent in the South Asian population (identified on 17 out of 30,440 chromosomes). The arginine at position 27 is highly conserved up to fruitfly considering 12 species and computational analyses of the p.Arg27Pro variant on protein structure and function indicate a deleterious effect (SIFT: damaging, PolyPhen-2:possibly damaging). Altogether, there is not enough evidence to classify the p.Arg27Pro variant with certainty.
Athena Diagnostics Inc	RCV000416180	SCV001144220	likely benign	not provided	2019-01-04	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001174176	SCV001337302	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002418035	SCV002678226	likely benign	Inborn genetic diseases	2020-02-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
PreventionGenetics, part of Exact Sciences	RCV003939903	SCV004749595	uncertain significance	HSPB1-related condition	2024-02-08	criteria provided, single submitter	clinical testing	The HSPB1 c.80G>C variant is predicted to result in the amino acid substitution p.Arg27Pro. This variant was reported in an individual with congenital heart defect who also carries a missense variant in the CCR3 gene (Table 2, Russell et al 2019. PubMed ID: 31453292.) In addition, this variant was reported twice in a Canadian cohort study of Charcot-Marie-Tooth disease and was classified as uncertain (Supplementary table 2, Volodarsky M et al 2020. PubMed ID: 32376792). This variant is reported in 0.056% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.