NM_004281.4(BAG3):c.230C>T (p.Pro77Leu) AND multiple conditions

Clinical significance:Uncertain significance (Last evaluated: Sep 24, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000472056.6

Allele description [Variation Report for NM_004281.4(BAG3):c.230C>T (p.Pro77Leu)]

NM_004281.4(BAG3):c.230C>T (p.Pro77Leu)

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.230C>T (p.Pro77Leu)
HGVS:
  • NC_000010.11:g.119669900C>T
  • NG_016125.1:g.23531C>T
  • NM_004281.3:c.230C>T
  • NM_004281.4:c.230C>TMANE SELECT
  • NP_004272.2:p.Pro77Leu
  • NP_004272.2:p.Pro77Leu
  • LRG_742t1:c.230C>T
  • LRG_742:g.23531C>T
  • LRG_742p1:p.Pro77Leu
  • NC_000010.10:g.121429412C>T
  • O95817:p.Pro77Leu
Protein change:
P77L
Links:
UniProtKB: O95817#VAR_066777; dbSNP: rs141355480
NCBI 1000 Genomes Browser:
rs141355480
Molecular consequence:
  • NM_004281.3:c.230C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004281.4:c.230C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Myofibrillar myopathy, BAG3-related (MFM6)
Synonyms:
MYOPATHY, MYOFIBRILLAR, 6
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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000550829Invitaecriteria provided, single submitter
Uncertain significance
(Sep 24, 2020)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation.

Kobayashi Y, Yang S, Nykamp K, Garcia J, Lincoln SE, Topper SE.

Genome Med. 2017 Feb 6;9(1):13. doi: 10.1186/s13073-017-0403-7.

PubMed [citation]
PMID:
28166811
PMCID:
PMC5295186

Progressive multifocal leukoencephalopathy in an immunocompetent patient.

van der Kolk NM, Arts P, van Uden IW, Hoischen A, van de Veerdonk FL, Netea MG, de Jong BA.

Ann Clin Transl Neurol. 2016 Mar;3(3):226-32. doi: 10.1002/acn3.279.

PubMed [citation]
PMID:
27042682
PMCID:
PMC4774259
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000550829.7

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

Description

This sequence change replaces proline with leucine at codon 77 of the BAG3 protein (p.Pro77Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs141355480, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with a BAG3-related disease. However, it was reported in an individual affected with progressive multifocal leukoencephalopathy, a pathology for which no association with BAG3 has been suggested elsewhere (PMID: 27042682). ClinVar contains an entry for this variant (Variation ID: 162774). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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: Nov 27, 2021

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