Submissions for variant NM_000371.4(TTR):c.290C>A (p.Ser97Tyr)

dbSNP: rs121918071

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519257	SCV000616907	pathogenic	not provided	2018-07-09	criteria provided, single submitter	clinical testing	The S97Y pathogenic variant in the TTR gene (also reported as S77Y due to alternative nomenclature) has been published multiple times in association with polyneuropathy and amyloidosis (Wallace et al., 1988; Swiecicki et al. 2015; Fontana et al., 1988; Carr et al., 2016); however, no familial segregation data were provided in these publications. The S97Y variant was not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although the S97Y variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, and this residue is not conserved, in silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, electrophoresis gradient assays found that S97Y altered the stability of TTR tetramers (Altland et al., 2007).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000014364	SCV000696623	pathogenic	Amyloidosis, hereditary systemic 1	2016-04-15	criteria provided, single submitter	clinical testing	Variant summary: The TTR c.290C>A variant affects a conserved nucleotide, resulting in amino acid change from Ser to Tyr. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). Functional studies have shown Ser97Tyr (a.k.a. Tyr77) to have reduced conformational stability of monomers and tetramers. This variant was not found in 121366 control chromosomes. After the met30 mutation (176300.0001), the tyr77 mutation is the most prevalent in ATTR patients (OMIM). In addition, multiple reputable databases list this variant in assoication with hereditary amyloidosis. Taken together, this variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000014364	SCV000814489	pathogenic	Amyloidosis, hereditary systemic 1	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 97 of the TTR protein (p.Ser97Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary amyloidosis (PMID: 1981182, 2891727, 9748014, 9771673, 25997029, 26017327). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Ser77Tyr. ClinVar contains an entry for this variant (Variation ID: 13422). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TTR protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000742	SCV001157789	pathogenic	not specified	2018-08-02	criteria provided, single submitter	clinical testing	The TTR c.290C>A; p.Ser97Tyr variant (rs121918071), also known as Ser77Tyr, is reported in the literature in multiple individuals and families affected with polyneuropathy and amyloidosis (Bhatia 1993, Blanco-Jerez 1998, Dohrn 2013, Fontana 2015, Mariani 2015, Reilly 1995, Satier 1990, Swiecicki 2015, Wallace 1998). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 13422), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. Functional analyses of the variant protein show reduced stability of monomers and tetramers (Altland 2007). The serine at codon 97 is moderately conserved and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Based on available information, this variant is considered to be pathogenic. References: Altland K et al. Genetic microheterogeneity of human transthyretin detected by IEF. Electrophoresis. 2007 Jun;28(12):2053-64. Bhatia K et al. Transthyretin gene mutations in British and French patients with amyloid neuropathy. J Neurol Neurosurg Psychiatry. 1993 Jun;56(6):694-7. Blanco-Jerez CR et al. Transthyretin Tyr77 familial amyloid polyneuropathy: a clinicopathological study of a large kindred. Muscle Nerve. 1998 Nov;21(11):1478-85. Dohrn MF et al. Diagnostic hallmarks and pitfalls in late-onset progressive transthyretin-related amyloid-neuropathy. J Neurol. 2013 Dec;260(12):3093-108. Fontana M et al. Differential Myocyte Responses in Patients with Cardiac Transthyretin Amyloidosis and Light-Chain Amyloidosis: A Cardiac MR Imaging Study. Radiology. 2015 Nov;277(2):388-97. Mariani LL et al. Genotype-phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France. Ann Neurol. 2015 Dec;78(6):901-16. Reilly MM et al. Transthyretin gene analysis in European patients with suspected familial amyloid polyneuropathy. Brain. 1995 Aug;118 (Pt 4):849-56. Satier F et al. Diagnosis of familial amyloidotic polyneuropathy in France. Clin Genet. 1990 Dec;38(6):469-73. Swiecicki PL et al. Hereditary ATTR amyloidosis: a single-institution experience with 266 patients. Amyloid. 2015;22(2):123-31. Wallace MR et al. Identification of a new hereditary amyloidosis prealbumin variant, Tyr-77, and detection of the gene by DNA analysis. J Clin Invest. 1988 Jan;81(1):189-93. Zeldenrust SR. Genotype--phenotype correlation in FAP. Amyloid. 2012 Jun;19 Suppl 1:22-4.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001173289	SCV001336373	pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433454	SCV002751911	pathogenic	Cardiovascular phenotype	2022-04-14	criteria provided, single submitter	clinical testing	The p.S97Y pathogenic mutation (also known as c.290C>A and S77Y), located in coding exon 3 of the TTR gene, results from a C to A substitution at nucleotide position 290. The serine at codon 97 is replaced by tyrosine, an amino acid with dissimilar properties. This mutation has been identified in numerous individuals with TTR amyloidosis (Wallace MR et al. J. Clin. Invest., 1988 Jan;81:189-93; Blanco-Jerez CR et al. Muscle Nerve, 1998 Nov;21:1478-85; Mariani LL et al. Ann. Neurol., 2015 Dec;78:901-16; Rowczenio D et al. Hum. Mutat., 2019 Jan;40:90-96). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Athena Diagnostics	RCV000519257	SCV002771672	pathogenic	not provided	2023-09-19	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with clinical features of transthyretin-related amyloidosis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as Ser77Tyr. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments indicate this variant results in reduced tetramer stability compared to wild-type (PMID: 17503405).
Fulgent Genetics, Fulgent Genetics	RCV002504783	SCV002804467	likely pathogenic	Hyperthyroxinemia, dystransthyretinemic; Amyloidosis, hereditary systemic 1; Carpal tunnel syndrome 1	2021-11-15	criteria provided, single submitter	clinical testing
OMIM	RCV000014364	SCV000034613	pathogenic	Amyloidosis, hereditary systemic 1	1998-11-01	no assertion criteria provided	literature only