1-201365247-GA-AC

Position:

• chr1-201365247-GA-AC

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_Moderate

The NM_001276345.2(TNNT2):​c.354_355delinsGT​(p.His119Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.98

Genes affected

TNNT2 (HGNC:11949): (troponin T2, cardiac type) This gene encodes the cardiac isoform of troponin T. The encoded protein is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration. Mutations in this gene have been associated with familial hypertrophic cardiomyopathy as well as with dilated cardiomyopathy. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a chain Troponin T, cardiac muscle (size 296) in uniprot entity TNNT2_HUMAN there are 88 pathogenic changes around while only 9 benign (91%) in NM_001276345.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 1-201365247-GA-AC is Pathogenic according to our data. Variant chr1-201365247-GA-AC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 229336.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.354_355delinsGT	p.His119Tyr	missense_variant	10/17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.354_355delinsGT	p.His119Tyr	missense_variant	10/17		NM_001276345.2	ENSP00000499593	A2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 16, 2017

The c.324_325delinsGT (p.His109Tyr) variant in TNNT2 has not been reported in an y other individuals with cardiomyopathy, however another variant (c.325C>T) resu lting in the same amino acid change (p.His109Tyr) was identified by our laborato ry in one individual with early onset DCM, ventricular tachycardia and a family history of HCM and sudden death (Pugh 2014). Both variants are absent in large population databases. Parental testing for the c.324_325delinGT variant was nega tive indicating that the variant occurred de novo in this individual. In additio n, the histidine residue (His) at position 109 is highly conserved in mammals an d across evolutionary distant species and the change to amino acid Tyrosine (Tyr ) at this position is predicted to be pathogenic using a computational tool clin ically validated by our laboratory (Jordan 2011). In summary, although additiona l studies are required to fully establish its clinical significance, the p.His10 9Tyr variant is likely pathogenic. ACMG/AMP Criteria applied: PS2; PM2; PP3. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs876658027; hg19: chr1-201334375;