Variant: NM_001276345.2(TNNT2):c.851+1G>A

Version: 1.0
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CA005196

43673 (ClinVar)

Gene: TNNT2 (HGNC:7139)

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 1d86a007-768b-4b8c-be66-f13fd8f5d403

Approved on: 2025-11-14

Published on: 2025-11-14

HGVS expressions

NM_001276345.2:c.851+1G>A
NM_001276345.2(TNNT2):c.851+1G>A
NC_000001.11:g.201359622C>T
CM000663.2:g.201359622C>T
NC_000001.10:g.201328750C>T
CM000663.1:g.201328750C>T
NC_000001.9:g.199595373C>T
NG_007556.1:g.23056G>A
ENST00000455702.7:c.836+1G>A
ENST00000367318.10:c.821+1G>A
ENST00000367322.6:c.809+1G>A
ENST00000412633.3:c.812+1G>A
ENST00000422165.6:c.842+1G>A
ENST00000438742.6:c.800+1G>A
ENST00000651504.1:n.1312+1G>A
ENST00000656932.1:c.851+1G>A
ENST00000658476.1:c.886+1G>A
ENST00000660295.1:c.821+1G>A
ENST00000662159.1:c.*210+1G>A
ENST00000663843.1:c.*751+1G>A
ENST00000666449.1:c.*96+1G>A
ENST00000236918.11:c.851+1G>A
ENST00000360372.8:c.722+1G>A
ENST00000367315.6:c.830+1G>A
ENST00000367317.8:c.803+1G>A
ENST00000367318.9:c.821+1G>A
ENST00000367320.6:c.722+1G>A
ENST00000367322.5:c.812+1G>A
ENST00000421663.6:c.635+1G>A
ENST00000438742.5:c.803+1G>A
ENST00000458432.6:c.635+1G>A
ENST00000460780.5:n.1970+1G>A
ENST00000476888.5:n.268+1G>A
ENST00000491504.5:n.2060+1G>A
ENST00000509001.5:c.821+1G>A
NM_000364.3:c.842+1G>A
NM_001001430.2:c.821+1G>A
NM_001001431.2:c.812+1G>A
NM_001001432.2:c.803+1G>A
NM_001276345.1:c.851+1G>A
NM_001276346.1:c.722+1G>A
NM_001276347.1:c.821+1G>A
NM_000364.4:c.842+1G>A
NM_001001430.3:c.821+1G>A
NM_001001431.3:c.812+1G>A
NM_001001432.3:c.803+1G>A
NM_001276346.2:c.722+1G>A
NM_001276347.2:c.821+1G>A

Likely Pathogenic

• Met criteria codes: PP1_Strong PM2_Supporting PS3_Moderate

• Not Met criteria codes: PVS1 BS1 BP2 PM6 PS2 PS4 BA1

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TNNT2 Version 1.0.0

Evidence submitted by expert panel

Cardiomyopathy VCEP

NM_001276345.2(TNNT2):c.851+1G>A. This variant has been reported in individuals with HCM and other cardiomyopathies (LMM data, Thierfelder 1994 PMID: 8205619, Watkins 1995 PMID: 7898523, Varnava 2001 PMID: 11560853) and is absent from large population studies (PM2_supporting; gnomAdD v2.1). It is not statistically increased in individuals with cardiomyopathy compared to controls [OR lower 95% CI <5]. Therefore, the PS4 criterion has not been applied. The variant segregated with HCM in at least 13 affected relatives from one family (PP1_Strong; Thierfelder 1994 PMID: 8205619, Watkins 1995 PMID: 7898523). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. This alteration is shown to affect the second to last exon, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In vitro and in vivo functional studies provide some evidence that this variant affected protein function (PS3_Moderate; Thierfelder 1994 PMID: 8205619, Watkins 1996 PMID: 8958207, Tardiff 1998 PMID: 9637714, Mukherjea 1999 PMID: 10529204, Szczesna 2000 PMID: 10617660, Gafurov 2004 PMID: 15568820, Becker 2011 PMID: 21245263). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner based on PM2_Supporting, PP1_Strong and PS3_Moderate.

Met criteria codes

• PP1_Strong: The variant segregated with HCM in at least 13 affected relatives from one family (Thierfelder 1994 PMID: 8205619, Watkins 1995 PMID: 7898523)
• PM2_Supporting: Absent in gnomad (2.1 and 4.1)
• PS3_Moderate: In vitro and in vivo functional studies provide some evidence that this variant affected protein function (PS3_Moderate; Thierfelder 1994 PMID: 8205619, Watkins 1996 PMID: 8958207, Tardiff 1998 PMID: 9637714, Mukherjea 1999 PMID: 10529204, Szczesna 2000 PMID: 10617660, Gafurov 2004 PMID: 15568820, Becker 2011 PMID: 21245263)

Not Met criteria codes

• PVS1: Splicing impact, out of frame exon but LOF is not dx mechanism
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: This variant has been reported in individuals with HCM and other cardiomyopathies (LMM data, Thierfelder 1994 PMID: 8205619, Watkins 1995 PMID: 7898523, Varnava 2001 PMID: 11560853) and i sabsent from large population studies (gnomAdD v2.1). It is not statistically increased in individuals with cardiomyopathy compared to controls [OR lower 95% CI <5]. Therefore, the PS4 criterion has not been applied and the PM2_Supporting criterion has been applied (PM2_Supporting).
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline