ClinVar Miner

Submissions for variant NM_000371.4(TTR):c.190T>C (p.Phe64Leu) (rs138065384)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000155021 SCV000204704 uncertain significance not specified 2015-05-14 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000766993 SCV000209370 uncertain significance not provided 2016-12-15 criteria provided, single submitter clinical testing A variant of uncertain significance was identified in the TTR gene. The F64L variant has previously been reported in association with cardiac amyloidosis (Connors et al., 2009; Reddi et al., 2014; Rowczenio et al., 2014). F64L (reported as F44L due to alternate nomenclature) was initially reported in an African American patient with amyloidosis who also harbored a second missense variant on the opposite TTR allele (in trans) (Connors et al., 2009). The F64L (reported as F44L) variant has also been reported in a Caucasian individual with cardiac involvement in the Online Registry for Mutations in Hereditary Amyloidosis (Rowczenio et al., 2014). Additionally, this variant has also been observed in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, and has been classified in ClinVar as a variant of uncertain significance by another clinical laboratory (ClinVar SCV000204704.5; Landrum et al., 2016). The F64L variant was not observed at a significant frequency 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. Other missense variants in nearby residues (W61L, E62G, E62D, A65S, A65T, A65D) and at the same residue (F64Y, F64S) have been reported in the Human Gene Mutation Database in association with amyloidosis, amylodotic polyneuropathy, and cardiomyopathy (Stenson et al., 2014); however, the pathogenicity of these variants has not been definitively determined. In addition, the F64L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, this substitution occurs at a position where amino acids with similar properties to Phenylalanine are tolerated across species, and in silico algorithms are inconsistent in predicting an effect of this variant on protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000474349 SCV000541952 uncertain significance Amyloidogenic transthyretin amyloidosis 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 64 of the TTR protein (p.Phe64Leu). The phenylalanine residue is weakly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs138065384, ExAC 0.06%). This variant has been observed in an individual with amyloidosis (PMID: 19781421). However, in that individual pathogenic allele[s] were also identified in TTR, which suggests that this c.190T>C variant may not be the primary cause of disease. This variant has also been observed in an individual with hypertrophic cardiomyopathy (PMID: 27532257). This variant is also known as Phe44Leu in the literature. ClinVar contains an entry for this variant (Variation ID: 178280). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Phe64 amino acid residue in TTR. Other variant(s) that disrupt this residue have been observed in individuals with TTR-related conditions (PMID: 9818883, 11812437, 11866053), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.
Molecular Genetics Laboratory,London Health Sciences Centre RCV001173294 SCV001336378 likely pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing

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