Submissions for variant NM_001540.5(HSPB1):c.372C>G (p.His124Gln)

gnomAD frequency: 0.00003  dbSNP: rs145243219

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000558321	SCV000640212	likely pathogenic	Charcot-Marie-Tooth disease axonal type 2F	2024-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 124 of the HSPB1 protein (p.His124Gln). This variant is present in population databases (rs145243219, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of autosomal dominant Charcot-Marie-Tooth disease and/or distal hereditary motor neuropathy (PMID: 32376792; internal data). ClinVar contains an entry for this variant (Variation ID: 465273). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HSPB1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Athena Diagnostics	RCV000711974	SCV000842385	uncertain significance	not provided	2018-01-25	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001172546	SCV001335607	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
GeneDx	RCV000711974	SCV001820623	uncertain significance	not provided	2022-02-09	criteria provided, single submitter	clinical testing	Reported as a variant of uncertain significance in two patients with Charcot-Marie-Tooth disease in published literature (Volodarsky et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32376792)
CeGaT Center for Human Genetics Tuebingen	RCV000711974	SCV002563956	uncertain significance	not provided	2022-07-01	criteria provided, single submitter	clinical testing	HSPB1: PM1, PP3, PP4
MGZ Medical Genetics Center	RCV000558321	SCV002579513	uncertain significance	Charcot-Marie-Tooth disease axonal type 2F	2022-03-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002350273	SCV002620345	likely benign	Inborn genetic diseases	2021-08-18	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.