Submissions for variant NM_001018005.2(TPM1):c.82G>A (p.Asp28Asn)

gnomAD frequency: 0.00001  dbSNP: rs397516391

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036363	SCV000060015	uncertain significance	not specified	2017-09-21	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000766946	SCV000209346	uncertain significance	not provided	2019-01-09	criteria provided, single submitter	clinical testing	The Asp28Asn variant in the TPM1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Asp28Asn results in a semi-conservative amino acid substitution of a negatively charged Aspartic acid with a neutral, polar Asparagine at a position that is conserved across species. In silico analysis predicts Asp28Asn is possibly damaging to the protein structure/function. Mutations in nearby codons (Ala22Thr, Lys37Glu, Glu40Lys) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. The NHLBI ESP Exome Variant Server reports Asp28Asn was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. With the clinical and molecular information available at this time, we cannot definitively determine if Asp28Asn is a disease-causing mutation or a rare benign variant. The variant is found in HCM panel(s).
Ambry Genetics	RCV000621745	SCV000740023	uncertain significance	Cardiovascular phenotype	2021-12-06	criteria provided, single submitter	clinical testing	The c.82G>A (p.D28N) alteration is located in exon 1 (coding exon 1) of the TPM1 gene. This alteration results from a G to A substitution at nucleotide position 82, causing the aspartic acid (D) at amino acid position 28 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Center for Human Genetics, University of Leuven	RCV000768533	SCV000886852	uncertain significance	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769476	SCV000900871	uncertain significance	Cardiomyopathy	2019-09-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769476	SCV001360404	uncertain significance	Cardiomyopathy	2023-07-24	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 28 of the TPM1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 24793961, 25351510, 27532257, 31513939). This variant has been identified in 2/238332 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000768533	SCV004331551	uncertain significance	Hypertrophic cardiomyopathy	2023-07-19	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 43443). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 24793961, 27532257, 31513939). 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 sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 28 of the TPM1 protein (p.Asp28Asn).
All of Us Research Program, National Institutes of Health	RCV000768533	SCV004815431	uncertain significance	Hypertrophic cardiomyopathy	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 28 of the TPM1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in a few individuals affected with hypertrophic cardiomyopathy (PMID: 24793961, 25351510, 27532257). This variant has been identified in 2/238332 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000766946	SCV001740796	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000766946	SCV001968783	uncertain significance	not provided		no assertion criteria provided	clinical testing