NM_001540.5(HSPB1):c.404C>A (p.Ser135Tyr) AND Charcot-Marie-Tooth disease axonal type 2F

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 12, 2019
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000641078.8

Allele description [Variation Report for NM_001540.5(HSPB1):c.404C>A (p.Ser135Tyr)]

NM_001540.5(HSPB1):c.404C>A (p.Ser135Tyr)

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.404C>A (p.Ser135Tyr)

HGVS:

NC_000007.14:g.76303841C>A
NG_008995.1:g.6284C>A
NM_001540.5:c.404C>AMANE SELECT
NP_001531.1:p.Ser135Tyr
LRG_248t1:c.404C>A
LRG_248:g.6284C>A
NC_000007.13:g.75933158C>A
NM_001540.3:c.404C>A

Protein change:

S135Y

Links:

dbSNP: rs28939680

NCBI 1000 Genomes Browser:

rs28939680

Molecular consequence:

NM_001540.5:c.404C>A - 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
SCV000762696	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 12, 2019)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 27816334, 23963299, 15122254, 18832141, 17881652, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000762696

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 12, 2019)

germline

clinical testing

PubMed (6)
[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

Pilot phenotype and natural history study of hereditary neuropathies caused by mutations in the HSPB1 gene.

Rossor AM, Morrow JM, Polke JM, Murphy SM, Houlden H; INC-RDCRC., Laura M, Manji H, Blake J, Reilly MM.

Neuromuscul Disord. 2017 Jan;27(1):50-56. doi: 10.1016/j.nmd.2016.10.001. Epub 2016 Oct 8.

PubMed [citation]

PMID:: 27816334
PMCID:: PMC5260843

Targeted next-generation sequencing reveals further genetic heterogeneity in axonal Charcot-Marie-Tooth neuropathy and a mutation in HSPB1.

Ylikallio E, Johari M, Konovalova S, Moilanen JS, Kiuru-Enari S, Auranen M, Pajunen L, Tyynismaa H.

Eur J Hum Genet. 2014 Apr;22(4):522-7. doi: 10.1038/ejhg.2013.190. Epub 2013 Aug 21.

PubMed [citation]

PMID:: 23963299
PMCID:: PMC3953916

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000762696.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This variant has been reported in individuals affected with distal hereditary motor neuropathy and Charcot-Marie-Tooth disease (PMID: 27816334, 23963299, Invitae) and has been reported to segregate with Charcot-Marie-Tooth disease in a single family (PMID: 23963299). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with tyrosine at codon 135 of the HSPB1 protein (p.Ser135Tyr). The serine residue is highly conserved and there is a large physicochemical difference between serine and tyrosine. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Ser135Phe) has been determined to be pathogenic (PMID: 15122254, 18832141, 17881652). This suggests that the serine residue is critical for HSPB1 protein function and that other missense substitutions at this position may also be 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: Jun 23, 2024

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