rs121918071

Variant names:

• chr18-31595209-C-A
• rs121918071
• NM_000371.4:c.290C>A

Your query was ambiguous. Multiple possible variants found:

• chr18-31595209-C-A
• chr18-31595209-C-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_000371.4(TTR):​c.290C>A​(p.Ser97Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S97F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 5.98
• Publications: 32 publications found

Genes affected

TTR (HGNC:12405): (transthyretin) This gene encodes one of the three prealbumins, which include alpha-1-antitrypsin, transthyretin and orosomucoid. The encoded protein, transthyretin, is a homo-tetrameric carrier protein, which transports thyroid hormones in the plasma and cerebrospinal fluid. It is also involved in the transport of retinol (vitamin A) in the plasma by associating with retinol-binding protein. The protein may also be involved in other intracellular processes including proteolysis, nerve regeneration, autophagy and glucose homeostasis. Mutations in this gene are associated with amyloid deposition, predominantly affecting peripheral nerves or the heart, while a small percentage of the gene mutations are non-amyloidogenic. The mutations are implicated in the etiology of several diseases, including amyloidotic polyneuropathy, euthyroid hyperthyroxinaemia, amyloidotic vitreous opacities, cardiomyopathy, oculoleptomeningeal amyloidosis, meningocerebrovascular amyloidosis and carpal tunnel syndrome. [provided by RefSeq, Aug 2017]

TTR Gene-Disease associations (from GenCC):

• amyloidosis, hereditary systemic 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• familial amyloid neuropathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary ATTR amyloidosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• heart conduction disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• ATTRV122I amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000294516 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000371.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31595209-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1797565.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 108 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.0149 (below the threshold of 3.09). Trascript score misZ: 1.5458 (below the threshold of 3.09). GenCC associations: The gene is linked to familial amyloid neuropathy, amyloidosis, hereditary systemic 1, ATTRV122I amyloidosis, hereditary ATTR amyloidosis, heart conduction disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834
• PP5: Variant 18-31595209-C-A is Pathogenic according to our data. Variant chr18-31595209-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 13422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4	c.290C>A	p.Ser97Tyr	missense_variant	Exon 3 of 4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.290C>A	p.Ser97Tyr	missense_variant	Exon 3 of 4	1	NM_000371.4	ENSP00000237014.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112002

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000343967), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:3

Nov 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Apr 15, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Nov 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Jul 09, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). -

Sep 19, 2023

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). -

Charcot-Marie-Tooth disease Pathogenic:1

-

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Pathogenic:1

Aug 02, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Hyperthyroxinemia, dystransthyretinemic;C2751492:Amyloidosis, hereditary systemic 1;C5779776:Carpal tunnel syndrome 1 Pathogenic:1

Nov 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Jun 11, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;D;T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.3	M;M;.;.
PhyloP100		6.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.7	.;D;.;.
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0070	.;D;.;.
Sift4G	Benign	0.11	.;T;D;D
Polyphen		0.72	P;P;.;.
Vest4		0.61, 0.63, 0.85
MutPred		0.66		Loss of methylation at K100 (P = 0.0681);Loss of methylation at K100 (P = 0.0681);Loss of methylation at K100 (P = 0.0681);Loss of methylation at K100 (P = 0.0681);
MVP		0.97
MPC		1.5
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.91
Mutation Taster		=21/79	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121918071; hg19: chr18-29175172;