NM_001289808.2(CRYAB):c.376del (p.Ala126fs) AND Dilated cardiomyopathy 1II

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 17, 2023
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:: RCV002045122.5

Allele description [Variation Report for NM_001289808.2(CRYAB):c.376del (p.Ala126fs)]

NM_001289808.2(CRYAB):c.376del (p.Ala126fs)

Gene:

CRYAB:crystallin alpha B [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

11q23.1

Genomic location:

Preferred name:

NM_001289808.2(CRYAB):c.376del (p.Ala126fs)

HGVS:

NC_000011.10:g.111908916del
NG_009824.3:g.19807del
NG_033080.2:g.1181del
NM_001289807.1:c.376del
NM_001289808.2:c.376delMANE SELECT
NM_001330379.1:c.175del
NM_001368245.1:c.376del
NM_001368246.1:c.175del
NM_001885.3:c.376del
NP_001276736.1:p.Ala126fs
NP_001276737.1:p.Ala126fs
NP_001317308.1:p.Ala59fs
NP_001355174.1:p.Ala126fs
NP_001355175.1:p.Ala59fs
NP_001876.1:p.Ala126fs
LRG_407t1:c.376del
LRG_407t2:c.376del
LRG_407:g.19807del
LRG_407p1:p.Ala126fs
LRG_407p2:p.Ala126fs
NC_000011.9:g.111779640del

Protein change:

A126fs

Links:

dbSNP: rs2137378811

NCBI 1000 Genomes Browser:

rs2137378811

Molecular consequence:

NM_001289807.1:c.376del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001289808.2:c.376del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001330379.1:c.175del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001368245.1:c.376del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001368246.1:c.175del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001885.3:c.376del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Dilated cardiomyopathy 1II (CMD1II)
Identifiers:: MONDO: MONDO:0014073; MedGen: C3554649; Orphanet: 154; OMIM: 615184

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002296294	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 17, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 14681890, 21920752, 23194663, 26627873, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002296294

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 17, 2023)

germline

clinical testing

PubMed (5)
[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

Myofibrillar myopathy caused by novel dominant negative alpha B-crystallin mutations.

Selcen D, Engel AG.

Ann Neurol. 2003 Dec;54(6):804-10.

PubMed [citation]

PMID:: 14681890

A novel CRYAB mutation resulting in multisystemic disease.

Sacconi S, Féasson L, Antoine JC, Pécheux C, Bernard R, Cobo AM, Casarin A, Salviati L, Desnuelle C, Urtizberea A.

Neuromuscul Disord. 2012 Jan;22(1):66-72. doi: 10.1016/j.nmd.2011.07.004. Epub 2011 Sep 14.

PubMed [citation]

PMID:: 21920752

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV002296294.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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. This variant disrupts the region of the CRYAB protein between p.Asp109 and p.Gln151. Other variants in this region have been observed in individuals with autosomal dominant CRYAB-related conditions (PMID: 14681890, 21920752, 23194663, 26627873), which suggests that this may be a clinically significant region of the protein. ClinVar contains an entry for this variant (Variation ID: 1502229). This variant has not been reported in the literature in individuals affected with CRYAB-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala126Leufs*3) in the CRYAB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 50 amino acid(s) of the CRYAB protein.

#	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: Mar 5, 2024

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