NM_001267550.2(TTN):c.59926C>T (p.His19976Tyr) AND not specified

Clinical significance:Uncertain significance (Last evaluated: Mar 1, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000152270.3

Allele description [Variation Report for NM_001267550.2(TTN):c.59926C>T (p.His19976Tyr)]

NM_001267550.2(TTN):c.59926C>T (p.His19976Tyr)

Genes:
TTN-AS1:TTN antisense RNA 1 [Gene - HGNC]
TTN:titin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_001267550.2(TTN):c.59926C>T (p.His19976Tyr)
Other names:
p.H18335Y:CAT>TAT
HGVS:
  • NC_000002.12:g.178591978G>A
  • NG_011618.3:g.243825C>T
  • NG_051363.1:g.74152G>A
  • NM_001256850.1:c.55003C>T
  • NM_001267550.2:c.59926C>TMANE SELECT
  • NM_003319.4:c.32731C>T
  • NM_133378.4:c.52222C>T
  • NM_133432.3:c.33106C>T
  • NM_133437.4:c.33307C>T
  • NP_001243779.1:p.His18335Tyr
  • NP_001254479.2:p.His19976Tyr
  • NP_003310.4:p.His10911Tyr
  • NP_596869.4:p.His17408Tyr
  • NP_597676.3:p.His11036Tyr
  • NP_597681.4:p.His11103Tyr
  • LRG_391:g.243825C>T
  • NC_000002.11:g.179456705G>A
Protein change:
H10911Y
Links:
dbSNP: rs727503588
NCBI 1000 Genomes Browser:
rs727503588
Molecular consequence:
  • NM_001256850.1:c.55003C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001267550.2:c.59926C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003319.4:c.32731C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133378.4:c.52222C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133432.3:c.33106C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133437.4:c.33307C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000201115Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Uncertain significance
(May 1, 2014)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000237359GeneDxcriteria provided, single submitter
Uncertain significance
(Sep 30, 2013)
germlineclinical testing

Citation Link,

SCV001160292ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Uncertain significance
(Mar 1, 2019)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided11not providednot providednot providedclinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000201115.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

Variant classified as Uncertain Significance - Favor Benign. The His17408Tyr var iant in TTN has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this infor mation is not predictive enough to rule out pathogenicity. It should be noted th at several other species (armadillo, green seaturtle, painted turtle, and 5 fish es) carry a tyrosine (Tyr) at this position, suggesting that this change may be tolerated. This variant is located in the last three bases of the exon, which is part of the 5' splice region. Computational tools do not predict altered splici ng, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the His17408Tyr variant is uncert ain, the presence of this variant in other species suggests that it is more like ly to be benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From GeneDx, SCV000237359.5

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

Description

Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in DCM panel(s).

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

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV001160292.1

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

Description

The c.52222C>T; p.His17408Tyr variant (rs727503588) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall frequency of 0.03 percent in the East Asian population (identified on 6 out of 19,198 chromosomes). This variant is directly 5' to a canonical donor splice site, and though a variant of this adjacent base has been reported in dilated cardiomyopathy, the c.52222C>T has not been reported. This missense variant affects a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical splice site. Without functional mRNA splicing however, the p.His17408Tyr variant cannot be classified with certainty.

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

Last Updated: Sep 6, 2021

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