NM_001540.5(HSPB1):c.407G>T (p.Arg136Leu) AND Charcot-Marie-Tooth disease axonal type 2F

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 30, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000201072.9

Allele description [Variation Report for NM_001540.5(HSPB1):c.407G>T (p.Arg136Leu)]

NM_001540.5(HSPB1):c.407G>T (p.Arg136Leu)

Gene:

HSPB1:heat shock protein family B (small) member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q11.23

Genomic location:

Preferred name:

NM_001540.5(HSPB1):c.407G>T (p.Arg136Leu)

HGVS:

NC_000007.14:g.76303844G>T
NG_008995.1:g.6287G>T
NM_001540.5:c.407G>TMANE SELECT
NP_001531.1:p.Arg136Leu
LRG_248t1:c.407G>T
LRG_248:g.6287G>T
NC_000007.13:g.75933161G>T
NM_001540.3:c.407G>T

Protein change:

R136L

Links:

dbSNP: rs863225022

NCBI 1000 Genomes Browser:

rs863225022

Molecular consequence:

NM_001540.5:c.407G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Charcot-Marie-Tooth disease axonal type 2F (CMT2F)
Synonyms:: Charcot-Marie-Tooth disease type 2F; CMT 2F; Charcot-Marie-Tooth disease, neuronal, Type 2F; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011687; MedGen: C1847823; Orphanet: 99940; OMIM: 606595

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000255780	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Jul 17, 2015)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22176143, 21611841, 25547330, 26467025
SCV000832663	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 30, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 21611841, 22176143, 25547330, 26989944, 15122254, 20178975, 22521462, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000255780

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(Jul 17, 2015)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000832663

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 30, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

MRI findings, patterns of disease distribution, and muscle fat fraction calculation in five patients with Charcot-Marie-Tooth type 2 F disease.

Gaeta M, Mileto A, Mazzeo A, Minutoli F, Di Leo R, Settineri N, Donato R, Ascenti G, Blandino A.

Skeletal Radiol. 2012 May;41(5):515-24. doi: 10.1007/s00256-011-1199-y. Epub 2011 May 25.

PubMed [citation]

PMID:: 21611841

See all PubMed Citations (9)

Details of each submission

From Athena Diagnostics, SCV000255780.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000832663.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 136 of the HSPB1 protein (p.Arg136Leu). This variant is present in population databases (no rsID available, gnomAD no frequency). This missense change has been observed in individuals with features of Charcot-Marie-Tooth, type 2 (CMT2) disease and distal hereditary motor neuropathy (dHMN) (PMID: 21611841, 22176143, 25547330, 26989944). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217230). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HSPB1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg136 amino acid residue in HSPB1. Other variant(s) that disrupt this residue have been observed in individuals with HSPB1-related conditions (PMID: 15122254, 20178975, 22521462), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Aug 4, 2024

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