Submissions for variant NM_001018005.2(TPM1):c.82G>C (p.Asp28His)

gnomAD frequency: 0.00001  dbSNP: rs397516391

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036364	SCV000060016	uncertain significance	not specified	2017-12-01	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000766945	SCV000209347	uncertain significance	not provided	2023-02-16	criteria provided, single submitter	clinical testing	Identified in a patient with early-onset atrial fibrillation (AF) in published literature (Yoneda 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: 27532257, 33673806, 34495297, 34699384, 29192238, 33495597)
Ambry Genetics	RCV000620750	SCV000736927	uncertain significance	Cardiovascular phenotype	2023-05-03	criteria provided, single submitter	clinical testing	The p.D28H variant (also known as c.82G>C), located in coding exon 1 of the TPM1 gene, results from a G to C substitution at nucleotide position 82. The aspartic acid at codon 28 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Walsh R et al. Genet Med, 2017 Feb;19:192-203; Magrì D et al. J Clin Med, 2020 May;9:[ePub ahead of print]; Hathaway J et al. BMC Cardiovasc Disord, 2021 Mar;21:126). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000689264	SCV000816906	uncertain significance	Hypertrophic cardiomyopathy	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 28 of the TPM1 protein (p.Asp28His). This variant is present in population databases (rs397516391, gnomAD 0.06%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and/or atrial fibrillation (PMID: 27532257, 33673806, 34495297). ClinVar contains an entry for this variant (Variation ID: 43444). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001525527	SCV001735666	uncertain significance	Cardiomyopathy	2020-11-11	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with histidine at codon 28 of the TPM1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 1/31358 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001525527	SCV002042874	uncertain significance	Cardiomyopathy	2021-10-08	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV003447482	SCV004175277	uncertain significance	Hypertrophic cardiomyopathy 21	2022-11-09	criteria provided, single submitter	clinical testing	The TPM1 c.82G>C variant is classified as a VUS (PS4_Moderate, PM2) The TPM1 c.82G>C variant is a single nucleotide change in exon 1/10 of the TPM1 gene, which is predicted to change the amino acid aspartic acid at position 28 in the protein, to histidine. The variant has been reported in at least 8 probands with a clinical presentation of hypertrophic cardiomyopathy (PMID#27532257, #33673806, #34495297 and ClinVar) (PS4_Moderate). The variant is rare in population databases (gnomAD allele frequency = 0.00065%; 1 het) (PM2), is reported in dbSNP (rs397516391), is reported as disease causing in the HGMD database (CM1616794) and is reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar #43444). Segregation studies in at least 5 affected family member may aid in further classification of this variant.
Blueprint Genetics	RCV000766945	SCV000927987	likely pathogenic	not provided	2018-10-11	flagged submission	clinical testing