Submissions for variant NM_001018005.2(TPM1):c.673A>G (p.Ile225Val)

gnomAD frequency: 0.00001  dbSNP: rs193922410

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030569	SCV000053240	uncertain significance	not specified	2019-01-24	criteria provided, single submitter	clinical testing	Variant summary: TPM1 c.673A>G (p.Ile225Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246128 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.673A>G in individuals affected with Hypertrophic Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. This variant was previously classified as a VUS-possibly pathogenic variant that was converted during ClinVar submission to likely pathogenic in 2011. Based on the absence of any new evidence outlined above, the variant is now classified as uncertain significance.
GeneDx	RCV000159379	SCV000209325	uncertain significance	not provided	2014-03-30	criteria provided, single submitter	clinical testing	A variant of unknown significance has been identified in the TPM1 gene. The I225V variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The I225V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I225V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense mutations in nearby residues (S215L and D230N) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This result cannot be interpreted for diagnosis or used for family member screening at this time. The variant is found in HCM panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001208267	SCV001379646	uncertain significance	Hypertrophic cardiomyopathy	2023-05-05	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. This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 225 of the TPM1 protein (p.Ile225Val). This variant is present in population databases (rs193922410, gnomAD 0.0009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 36887). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149589	SCV003838408	uncertain significance	Cardiomyopathy	2022-03-02	criteria provided, single submitter	clinical testing