NM_004281.4(BAG3):c.100_107del (p.Thr34fs) AND not provided

Clinical significance:Likely pathogenic (Last evaluated: Jun 8, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000786108.3

Allele description [Variation Report for NM_004281.4(BAG3):c.100_107del (p.Thr34fs)]

NM_004281.4(BAG3):c.100_107del (p.Thr34fs)

Gene:
BAG3:BAG cochaperone 3 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
10q26.11
Genomic location:
Preferred name:
NM_004281.4(BAG3):c.100_107del (p.Thr34fs)
HGVS:
  • NC_000010.11:g.119651775_119651782del
  • NG_016125.1:g.5406_5413del
  • NM_004281.4:c.100_107delMANE SELECT
  • NP_004272.2:p.Thr34fs
  • LRG_742:g.5406_5413del
  • NC_000010.10:g.121411287_121411294del
  • NC_000010.10:g.121411287_121411294delACCGGCTG
  • NM_004281.3:c.100_107delACCGGCTG
  • p.Thr34AlafsX21
Protein change:
T34fs
Links:
dbSNP: rs727505283
NCBI 1000 Genomes Browser:
rs727505283
Molecular consequence:
  • NM_004281.4:c.100_107del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000924756Stanford Center for Inherited Cardiovascular Disease, Stanford Universityno assertion criteria providedLikely pathogenic
(Jan 3, 2017)
germlineprovider interpretation

SCV001766176GeneDxcriteria provided, single submitter
Likely pathogenic
(Jun 8, 2021)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedprovider interpretation

Details of each submission

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000924756.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedprovider interpretationnot provided

Description

Given the strong evidence implicating frameshift variants in BAG3 in disease and the rarity of the variant, we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). There are no published reports of the variant. The normal sequence with the bases that are deleted in braces is: GCAG[ACCGGCTG]GCCC. Given how early on the variant occurs it most likely leads to nonsense mediated decay and no protein product. As reviewed above, null variants in BAG3 have been implicated in disease and are very rare in the general population. The variant is not listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of September 24th, 2015). However, the methods used with that dataset may miss some indels of this size. The variant was also absent in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. As with ExAC, it is unclear how well the methods used in that dataset account for potential indels.

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

From GeneDx, SCV001766176.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease

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

Last Updated: Nov 27, 2021

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