Submissions for variant NM_001018005.2(TPM1):c.62G>T (p.Arg21Leu)

gnomAD frequency: 0.00002  dbSNP: rs730881151

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000168980	SCV000209344	uncertain significance	not provided	2023-07-06	criteria provided, single submitter	clinical testing	Identified in an individual who suffered sudden death at rest and harbored additional cardiogenetic variants (Iglesias et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29105867, 28138913, 28797094, 28771489, 34426522, 33642254, 31983221, 33919104, 30681346)
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000201492	SCV000256207	likely pathogenic	Hypertrophic cardiomyopathy 3		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000244434	SCV000318597	uncertain significance	Cardiovascular phenotype	2021-09-20	criteria provided, single submitter	clinical testing	The p.R21L variant (also known as c.62G>T), located in coding exon 1 of the TPM1 gene, results from a G to T substitution at nucleotide position 62. The arginine at codon 21 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in individuals from hypertrophic cardiomyopathy (HCM) and sudden death cohots; however, in some cases clinical detail was limited or co-occurring variants were detected (Alejandra Restrepo-Cordoba M et al. J Cardiovasc Transl Res, 2017 Feb;10:35-46; Mademont-Soler I et al. PLoS One. 2017 Aug;12(8):e0181465; Mendes de Almeida R et al. PLoS ONE, 2017 Aug;12:e0182946; Iglesias M et al. J Clin Med. 2021 Apr;10(9)). In one study, this variant was detected in several HCM cases from Spain and Portugal, was reported to segregate with disease, and was considered associated with late-onset, incomplete penetrance, and milder clinical course; however, details were not available and several cases had co-occurring variants (Lamounier Junior A. Rev Esp Cardiol (Engl Ed). 2021 Feb. doi: 10.1016/j.rec.2021.01.001 [Online ahead of print]). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000524610	SCV000623810	likely pathogenic	Hypertrophic cardiomyopathy	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 21 of the TPM1 protein (p.Arg21Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 28138913, 33642254; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 181678). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Blueprint Genetics	RCV000168980	SCV000927905	uncertain significance	not provided	2018-09-01	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000524610	SCV000995152	uncertain significance	Hypertrophic cardiomyopathy	2018-11-22	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000168980	SCV002502459	uncertain significance	not provided	2021-12-03	criteria provided, single submitter	clinical testing
Mendelics	RCV002247554	SCV002516110	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252010	SCV002522942	uncertain significance	See cases	2021-12-06	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2, PP3
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000201492	SCV002769493	uncertain significance	Hypertrophic cardiomyopathy 3	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, although it has been suggested that that HCM is caused by gain of function missense variants while DCM is caused by loss of function missense variants (PMID: 31270709). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Variants in this gene have been associated with late-onset disease or incomplete penetrance (PMIDs: 33642254; 32882290, 32731933). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to leucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (5 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. The p.(Arg21His) variant has been reported in one HCM individual, while the p.(Arg21Cys) variant has been reported in two unrelated HCM individuals, although there is limited information provided (PMIDs: 16005017, 21239446). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified multiple times as VUS and has been identified in multiple individuals with HCM and other cardiac-related phenotypes, a number of whom also harboured a likely pathogenic or pathogenic variant in MYBPC3 or VUS in other cardiac genes (personal communication from ClinVar submitters; PMIDs: 28771489, 33919104, 33642254, 33495597). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149965	SCV003838402	uncertain significance	Cardiomyopathy	2022-07-22	criteria provided, single submitter	clinical testing
New York Genome Center	RCV003448274	SCV004176058	likely pathogenic	Hypertrophic cardiomyopathy 3; Dilated cardiomyopathy 1Y	2023-06-22	criteria provided, single submitter	clinical testing	The c.62G>T variant in TPM1 has previously been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) and sudden death in homozygous, heterozygous, and also found to co-occur with additional gene variants [PMID: 28138913, 28797094, 33919104, 33642254]. Additionally, this variant was reported to be absent in controls, was found to segregate with disease, and associated with late-onset, incomplete penetrance, and milder clinical course [PMID: 33642254]. This variant has been deposited in ClinVar [ClinVar ID: 181678] as Variant of Uncertain Significance/Likely Pathogenic. The c.62G>T variant is observed in 22 alleles (~0.004% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.62G>T variant in TPM1 is located in exon 1 of this 10-exon gene and predicted to replace an evolutionarily conserved arginine amino acid with leucine at position 21 in the N-terminal region of the encoded protein which is reported to be crucial for binding of TPM1 with actin protein [PMID:26873245, 11964245, 30240712, 33642254]. In silico predictions are in favor of damaging effect for p.(Arg21Leu) [(CADD v1.6 = 24.3, REVEL = 0.773)]; however, there are no functional studies to support or refute these predictions. Another missense substitution affecting the same protein residue p.(Arg21His) has previously been identified in an individual with hypertrophic cardiomyopathy and shown to be functionally damaging [PMID: 21239446, 29105867]. Based on available evidence this c.62G>T p.(Arg21Leu) variant identified in TPM1 is classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV003149965	SCV004360031	likely pathogenic	Cardiomyopathy	2023-09-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 21 in the actin binding region of the TPM1 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in over 30 families affected with hypertrophic cardiomyopathy (PMID: 33642254). Overall, 39 heterozygous affected individuals (age range 11-73 years) and 5 homozygous individuals (age range 40-71 years) were observed in this study with highly variable age of onset, as well as 22 heterozygous unaffected individual (age range 9-80 years). This variant has been shown to segregate with disease in 8 families (11 informative segregations) (PMID: 33642254). This variant has also been reported in 4 other unrelated heterozygous individuals affected with hypertrophic cardiomyopathy (PMID: 28138913, 28771489, 28797094, 33642254, 37498360), one of whom carried a pathogenic variant in the MYBPC3 gene (PMID: 28771489). This variant has also been reported in an individual affected with sudden death (PMID: 33642254). This variant has been identified in 5/246812 chromosomes (5/34311of Latino) in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.