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

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jan 28, 2022
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:
RCV003227676.1

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

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

Genes:
LOC126806424:CDK7 strongly-dependent group 2 enhancer GRCh37_chr2:179456337-179457536 [Gene]
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
  • NM_001267550.1:c.59926C>T
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)

Name:
Dilated cardiomyopathy 1G (CMD1G)
Identifiers:
MONDO: MONDO:0011400; MedGen: C1858763; Orphanet: 154; OMIM: 604145
Name:
Hypertrophic cardiomyopathy 9
Synonyms:
Familial hypertrophic cardiomyopathy 9
Identifiers:
MONDO: MONDO:0013412; MedGen: C1861065; OMIM: 613765

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003925300New York Genome Center
criteria provided, single submitter

(NYGC Assertion Criteria 2020)		Uncertain significance
(Jan 28, 2022) 		germlineclinical testing

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Details of each submission

From New York Genome Center, SCV003925300.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The c.59926C>T (p.His19976Tyr) missense variant identified in the TTN gene has not been reported in affected individuals in the literature. The variant has 0.00003946 allele frequency in the gnomAD (v3.1.2) database (6 out of 152058 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the populations represented in that database. The variant has been reported in the ClinVar database as a variant of uncertain significance (4 entries) and likely benign (2 entries) (Variation ID: 165933). The variant affects a moderately conserved residue (His19976) located in the A-band domain of the TTN gene (PMID: 25589632). The TTN gene has 363 exons (transcript NM_001267550.2), and this variant alters the last nucleotide of exon 302 suggesting that it may affect the normal mRNA splicing. In silico tools provide conflicting predictions about potential pathogenicity of this variant (CADD score = 22.5,REVEL score = 0.082, Splice AI = 0.00, TRAP = 0.551]. Based on the available evidence, the c.59926C>T (p.His19976Tyr) missense variant identified in the TTN gene is reported as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Nov 30, 2024