NM_004281.4(BAG3):c.1408C>A (p.Pro470Thr) AND multiple conditions

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Feb 18, 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:
RCV003023580.2

Allele description [Variation Report for NM_004281.4(BAG3):c.1408C>A (p.Pro470Thr)]

NM_004281.4(BAG3):c.1408C>A (p.Pro470Thr)

Gene:
BAG3:BAG cochaperone 3 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
10q26.11
Genomic location:
Preferred name:
NM_004281.4(BAG3):c.1408C>A (p.Pro470Thr)
HGVS:
  • NC_000010.11:g.119676962C>A
  • NG_016125.1:g.30593C>A
  • NM_004281.4:c.1408C>AMANE SELECT
  • NP_004272.2:p.Pro470Thr
  • NP_004272.2:p.Pro470Thr
  • LRG_742t1:c.1408C>A
  • LRG_742:g.30593C>A
  • LRG_742p1:p.Pro470Thr
  • NC_000010.10:g.121436474C>A
  • NM_004281.3:c.1408C>A
Protein change:
P470T
Molecular consequence:
  • NM_004281.4:c.1408C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Myofibrillar myopathy 6
Synonyms:
Myofibrillar myopathy, BAG3-related
Identifiers:
MONDO: MONDO:0013061; MedGen: C2751831; Orphanet: 199340; OMIM: 612954
Name:
Dilated cardiomyopathy 1HH (CMD1HH)
Identifiers:
MONDO: MONDO:0013479; MedGen: C3151293; Orphanet: 154; OMIM: 613881

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003318433Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Feb 18, 2023) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks.

Meister-Broekema M, Freilich R, Jagadeesan C, Rauch JN, Bengoechea R, Motley WW, Kuiper EFE, Minoia M, Furtado GV, van Waarde MAWH, Bird SJ, Rebelo A, Zuchner S, Pytel P, Scherer SS, Morelli FF, Carra S, Weihl CC, Bergink S, Gestwicki JE, Kampinga HH.

Nat Commun. 2018 Dec 17;9(1):5342. doi: 10.1038/s41467-018-07718-5.

PubMed [citation]
PMID:
30559338
PMCID:
PMC6297355

A family with adult-onset myofibrillar myopathy with BAG3 mutation (P470S) presenting with axonal polyneuropathy.

Hamaguchi M, Kokubun N, Inoue M, Komagamine T, Aoki R, Nishino I, Hirata K.

Neuromuscul Disord. 2020 Sep;30(9):727-731. doi: 10.1016/j.nmd.2020.07.012. Epub 2020 Aug 1.

PubMed [citation]
PMID:
32859500
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV003318433.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 470 of the BAG3 protein (p.Pro470Thr). This variant is present in population databases (rs756020699, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with BAG3-related conditions. 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 not expected to disrupt BAG3 protein function. This variant disrupts the p.Pro470 amino acid residue in BAG3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30559338, 32859500). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 5, 2024