NM_001276345.2(TNNT2):c.601-1G>A AND not provided

Clinical significance:Uncertain significance (Last evaluated: Jul 25, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000223749.2

Allele description [Variation Report for NM_001276345.2(TNNT2):c.601-1G>A]

NM_001276345.2(TNNT2):c.601-1G>A

Gene:
TNNT2:troponin T2, cardiac type [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q32.1
Genomic location:
Preferred name:
NM_001276345.2(TNNT2):c.601-1G>A
HGVS:
  • NC_000001.11:g.201362395C>T
  • NG_007556.1:g.20283G>A
  • NM_000364.4:c.601-373G>A
  • NM_001001430.3:c.571-1G>A
  • NM_001001431.3:c.571-373G>A
  • NM_001001432.3:c.556-4G>A
  • NM_001276345.2:c.601-1G>AMANE SELECT
  • NM_001276346.2:c.481-373G>A
  • NM_001276347.2:c.571-1G>A
  • LRG_431t1:c.601-1G>A
  • LRG_431:g.20283G>A
  • NC_000001.10:g.201331523C>T
  • NM_001001430.1:c.571-1G>A
  • NM_001001430.2:c.571-1G>A
  • NM_001276347.1:c.571-1G>A
Links:
dbSNP: rs483352835
NCBI 1000 Genomes Browser:
rs483352835
Molecular consequence:
  • NM_000364.4:c.601-373G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001001431.3:c.571-373G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001001432.3:c.556-4G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001276346.2:c.481-373G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001001430.3:c.571-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001276345.2:c.601-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001276347.2:c.571-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
Observations:
2

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000209251GeneDxcriteria provided, single submitter
Uncertain significance
(Jul 25, 2018)
germlineclinical testing

Citation Link,

SCV000280530Stanford Center for Inherited Cardiovascular Disease, Stanford Universityno assertion criteria providedLikely pathogenic
(Sep 30, 2010)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided2not providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000209251.13

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

Description

The c.571-1 G>A variant of uncertain significance in the TNNT2 gene has been identified in one individual with early onset, severe HCM who also harbored a pathogenic variant in the MYH7 gene, and in one individual with DCM (Van Driest et al., 2004; Rani et al., 2014). The c.571-1 G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This variant destroys the canonical splice acceptor site in intron 11 and is predicted to cause abnormal gene splicing. However, the majority of pathogenic variants in the TNNT2 gene are missense variants (Stenson et al., 2014), indicating that haploinsufficiency of TNNT2 may not be sufficient to cause cardiomyopathy.

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

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280530.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testingnot provided

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. IVS 11-1G>A. This variant changes the last base of the intron for a G to an A. This base is a key part of the splicing consensus sequence and is essentially always a G. Thus a change from G to A would be highly likely to affect splicing. Consistent with this expectation, Van Driest et al (2004) reported alternative splicing causing an in-frame deletion of a glutamine in a patient with this mutation. That patient also had a mutation in MYH7 (p.Arg453Cys) and a clinical history consistent with multiple mutations (infantile onset HCM with severe hypertrophy (38mm) and VT). While most TNNT2 mutations are missense, four other single amino acid deletions have been reported in association with HCM. No segregation data on this variant were reported by either the testing lab or Van Dreist et al. The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~5300 Caucasian and African American individuals (as of 3/6/2012). Note that this dataset does not match the patient's ancestry (Samoan). Of note, there are no splicing variants in TNNT2 in this data set.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided2not providednot providednot provided

Last Updated: Jul 7, 2021

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