Variant: NM_001018005.2(TPM1):c.842T>C (p.Met281Thr)

Version: 1.0
JSON-LD PDF

CA018416

31885 (ClinVar)

Gene: TPM1 (HGNC:7168)

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 6debff91-5fa6-43cd-ba3f-4f21edf1ee18

Approved on: 2025-11-13

Published on: 2025-11-13

HGVS expressions

NM_001018005.2(TPM1):c.842T>C (p.Met281Thr)
NM_001018005.2:c.842T>C
NC_000015.10:g.63064133T>C
CM000677.2:g.63064133T>C
NC_000015.9:g.63356332T>C
CM000677.1:g.63356332T>C
NC_000015.8:g.61143385T>C
NG_007557.1:g.26495T>C
ENST00000558868.6:n.1555+1488T>C
ENST00000559831.6:c.*191+1488T>C
ENST00000560131.2:n.2408T>C
ENST00000560615.6:c.394+1488T>C
ENST00000561395.6:c.*261T>C
ENST00000651622.2:c.734T>C
ENST00000705544.1:c.529T>C
ENST00000317516.12:c.664+1488T>C
ENST00000334895.10:c.664+1488T>C
ENST00000357980.9:c.898+1488T>C
ENST00000403994.9:c.842T>C
ENST00000404484.9:c.664+1488T>C
ENST00000558910.3:c.734T>C
ENST00000559281.6:c.734T>C
ENST00000559397.6:c.772+1488T>C
ENST00000560970.6:c.842T>C
ENST00000561266.6:c.842T>C
ENST00000644204.1:n.794+1488T>C
ENST00000651344.1:n.1288+1488T>C
ENST00000651577.1:c.394+1488T>C
ENST00000651590.1:c.664+1488T>C
ENST00000651622.1:c.174T>C
ENST00000651704.1:c.394+1488T>C
ENST00000267996.11:c.772+1488T>C
ENST00000288398.10:c.842T>C
ENST00000317516.11:c.664+1488T>C
ENST00000334895.9:c.664+1488T>C
ENST00000357980.8:c.898+1488T>C
ENST00000358278.7:c.772+1488T>C
ENST00000403994.7:c.842T>C
ENST00000404484.8:c.664+1488T>C
ENST00000558072.5:n.291+1488T>C
ENST00000558264.5:c.*191+1488T>C
ENST00000558347.5:c.*180+1488T>C
ENST00000558544.5:c.*380+1488T>C
ENST00000558910.2:c.87T>C
ENST00000559108.1:n.240+1488T>C
ENST00000559281.5:c.734T>C
ENST00000559397.5:c.772+1488T>C
ENST00000559556.5:c.772+1488T>C
ENST00000560131.1:n.330T>C
ENST00000560445.1:c.187-1828T>C
ENST00000560970.5:c.784T>C
ENST00000560975.5:n.2621+1488T>C
ENST00000561266.5:c.658T>C
ENST00000561395.5:c.468T>C
NM_000366.5:c.842T>C
NM_001018004.1:c.772+1488T>C
NM_001018005.1:c.842T>C
NM_001018006.1:c.772+1488T>C
NM_001018007.1:c.772+1488T>C
NM_001018008.1:c.664+1488T>C
NM_001018020.1:c.772+1488T>C
NM_001301244.1:c.842T>C
NM_001301289.1:c.664+1488T>C
NM_001330344.1:c.664+1488T>C
NM_001330346.1:c.734T>C
NM_001330351.1:c.664+1488T>C
NM_001365776.1:c.772+1488T>C
NM_001365777.1:c.772+1488T>C
NM_001365778.1:c.898+1488T>C
NM_001365779.1:c.842T>C
NM_001365780.1:c.664+1488T>C
NM_001365781.1:c.734T>C
NM_001365782.1:c.734T>C
NM_000366.6:c.842T>C
NM_001018004.2:c.772+1488T>C
NM_001018006.2:c.772+1488T>C
NM_001018007.2:c.772+1488T>C
NM_001018008.2:c.664+1488T>C
NM_001018020.2:c.772+1488T>C
NM_001301244.2:c.842T>C
NM_001301289.2:c.664+1488T>C
NM_001330344.2:c.664+1488T>C
NM_001330346.2:c.734T>C
NM_001330351.2:c.664+1488T>C
NM_001365781.2:c.734T>C

Uncertain Significance

• Met criteria codes: PM2_Supporting PS4_Supporting PP3 PP2

• Not Met criteria codes: BA1 BP4 BP5 BS3 BS4 BS1 PP1 PS3 PS2 PS1 PM6 PVS1 PM4 PM1 PM5

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TPM1 Version 1.0.0

Evidence submitted by expert panel

Cardiomyopathy VCEP

NM_001018005.2(TPM1):c.842T>C (p.Met281Thr) - This variant has been reported in individuals with HCM (PMIDs: 12860912, 18533079, 21835320, 25524337, 27532257) and is statistically increased in individuals with cardiomyopathy compared to controls [OR lower 95% CI >5]. Therefore, the PS4_Supporting criterion has been applied. This variant is present in gnomAD (v2.1.1), but did meet the threshold for PM2_Supporting. This variant lies in a gene where variants are statistically more likely to be disease-associated (PP2; PMID: 30696458). Computational prediction tools suggest that this variant may impact the protein (REVEL score >0.7; PP3). In summary, this variant is classified as Uncertain Significance for HCM in an autosomal dominant manner based on PS4_Supporting, PM2_Supporting, PP2, and PP3.

Met criteria codes

• PM2_Supporting: gnomAD v2.1.1: European non-Finnish AC=1, AN=113,468. Not detected in any other population.
• PS4_Supporting: Disease specific rules: Case-control odds ratio (OR) calculations (Lower 95% CI of OR ≥5 SUPPORTING; ≥10 MODERATE; ≥20 STRONG) OR calculated based on counts in the literature and ClinVar Case data Literature: 4 cases (not including LMM-counted under ClinVar) ClinVar: entries from 7 centres (including LMM). Count as minimum 7 occurrences? Estimated case count= min 11 Estimated no cases tested=minimum ~15,000 Control data Variant found in African population in gnomAD v3.1 (AC=2 AN=41,464). The Total gnomAD population used as denominator for case vs control analysis, as this was considered to reflect the ancestries represented in the case population. However, this might mean we are underestimating the frequency of this variant in controls. gnomAD (Total data from v3.1) number with variant=2 , number without variant= 76,116 OR:27.91 95% CI [6.19-125.93] Note: On initial review, using gnomAD v2.1.1 data only. PS4_supporting was applied. This variant has been reported in individuals with HCM (PMIDs: 12860912, 18533079, 21835320, 25524337, 27532257) and is statistically increased in individuals with cardiomyopathy compared to controls [OR lower 95% CI >5]. Therefore, PS4_Supporting criteria has been applied.
• PP3: 1/11/23: REVEL: 0.706 REVEL:0.846 Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity (PP3).
• PP2: New guidelines: PP2_supporting applies for this TPM1 in context of HCM. This variant lies in a gene where variants are statistically more likely to be disease-associated (PP2; PMID: 30696458).

Not Met criteria codes

• BA1: gnomAD v2.1.1: FAF < 0.1% BA1 threshold.
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: gnomAD v2.1.1: FAF < 0.02% BS1 threshold.
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: 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
• PS1: 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
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline