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

gnomAD frequency: 0.00019  dbSNP: rs138065384

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155021	SCV000204704	uncertain significance	not specified	2021-04-06	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Phe64Leu variant in TTR has been reported in at least 17 individuals with amyloidosis, including one homozygote and one compound heterozygote for another pathogenic TTR missesne variant which suggests that this variant may not be the primary cause of disease in this individual.(Ferlini 1996 PMID: 8721565, Comenzo 2006 PMID: 16439680, Connors 2009 PMID: 19781421, Cappellari 2011 PMID: 21692911, Klein 2011 PMID: 20937937, Rapezzi 2011 PMID: 21679902, Luigetti 2012 PMID: 22592564). It has also been reported in two individuals with hypertrophic cardiomyopathy (Walsh 2017 PMID: 27532257 Hoss 2020 PMID: 32150461, LMM data). It has been identified in 0.06% (14/24960) of African American chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 178280). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that this variant impacts protein function (Altland 2007 PMID: 17503405); however, these types of assays may not accurately represent biological function. Additional variants involving this codon (p.Phe64Ser and p.Phe64Tyr) have been identified in individuals with amyloidosis. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain: ACMG/AMP Criteria applied: PS4, PS3_Supporting.
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	likely benign	Familial amyloid neuropathy	2023-12-17	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001173294	SCV001336378	likely pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798511	SCV002042741	uncertain significance	Cardiomyopathy	2020-07-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408691	SCV002723277	uncertain significance	Cardiovascular phenotype	2022-07-13	criteria provided, single submitter	clinical testing	The p.F64L variant (also known as c.190T>C), located in coding exon 2 of the TTR gene, results from a T to C substitution at nucleotide position 190. The phenylalanine at codon 64 is replaced by leucine, an amino acid with highly similar properties. This variant (also described as p.F44L) has been reported in an individual with amyloidosis, who also had an additional TTR variant detected (Connors LH et al. Am. Heart J., 2009 Oct;158:607-14). This variant was also reported in one individual from a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is well 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.
Athena Diagnostics Inc	RCV000766993	SCV004229419	likely pathogenic	not provided	2023-06-14	criteria provided, single submitter	clinical testing	The frequency of this variant is statistically more frequent in affected individuals than in the general population and/or healthy controls (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple unrelated individuals with hereditary transthyretin-related amyloidosis, including individuals with cardiac transthyretin amyloidosis. In Italy, it has been suggested to be one of the most common variants associated with FAP (familial amyloidotic polyneuropathy) (PMID: 36289657). Multiple affected individuals have been reported with missense changes at this codon, suggesting this variant also causes disease. This variant is also referred to as F44L and F84L in published literature.