ClinVar Miner

Submissions for variant NM_000371.3(TTR):c.290C>A (p.Ser97Tyr) (rs121918071)

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Total submissions: 6
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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).
Integrated Genetics/Laboratory Corporation of America RCV000014364 SCV000696623 pathogenic Amyloidogenic transthyretin amyloidosis 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.
Invitae RCV000014364 SCV000814489 pathogenic Amyloidogenic transthyretin amyloidosis 2019-08-21 criteria provided, single submitter clinical testing This sequence change replaces serine with tyrosine at codon 97 of the TTR protein (p.Ser97Tyr). The serine residue is moderately conserved and there is a large physicochemical difference between serine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals and families with a large number of individuals affected with hereditary amyloidosis (PMID: 2891727, 1981182, 9771673, 9748014, 26017327, 25997029). This variant is also known as p.Ser77Tyr in the literature. ClinVar contains an entry for this variant (Variation ID: 13422). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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
OMIM RCV000014364 SCV000034613 pathogenic Amyloidogenic transthyretin amyloidosis 1998-11-01 no assertion criteria provided literature only

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