rs121918100

Positions:

• chr18-31595184-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000371.4(TTR):​c.265T>C​(p.Tyr89His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. Y89I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.06

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a strand (size 7) in uniprot entity TTHY_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) 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 chr18-31595183-ATA-AAT is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 18-31595184-T-C is Pathogenic according to our data. Variant chr18-31595184-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31595184-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4	c.265T>C	p.Tyr89His	missense_variant	3/4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.265T>C	p.Tyr89His	missense_variant	3/4	1	NM_000371.4	ENSP00000237014.4
TTR	ENST00000649620.1	c.265T>C	p.Tyr89His	missense_variant	5/6			ENSP00000497927.1
TTR	ENST00000610404.5	c.169T>C	p.Tyr57His	missense_variant	3/4	5		ENSP00000477599.2
TTR	ENST00000541025.2	n.291T>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 28, 2020	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect TTR protein function (PMID: 15820680). This variant has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 19491989, 19922332, 26156087, 31257920, 31718691). This variant is also known as Y69H or Tyr69His in the literature. ClinVar contains an entry for this variant (Variation ID: 13466). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with histidine at codon 89 of the TTR protein (p.Tyr89His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 27, 2003	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Jul 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 15, 2016	Variant summary: Variant affects a conserved nucleotide and results in a replacement of a large size and aromatic (Y) with a medium size and polar Histidine (H). 4/4 in silico tools predict the variant to be disease causing. It is absent from the large and broad cohorts of the ExAC project while it was reported in several ATTR patients. Patients presented with a wide range of symptoms including oculoleptomeningeal amyloidosis, seizures and steadily progressing dementia with amyloid deposit findings at autopsy indicating pathogenicity. One database classifies variant as pathogenic. Considering all evidence, the variant was classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 26, 2019

The TTR c.265T>C;p.Tyr89His variant (rs121918100), also known as Tyr69His in alternative nomenclature, has been published in individuals with oculoleptomenmingeal amyloidosis or ataxia and dementia and been demonstrated to segregate with disease in at least one family (Blevins 2003, Schweitzer 2009, Ziskin 2015). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at amino acid 89 is highly conserved, and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Functional studies further suggest the variant protein has decreased thermodynamic stability and slow tetramer dissociation (Sekijima 2005), although it is not clear that these properties contribute to pathogenesis. Considering available information, the p.Tyr89His variant is considered to be likely pathogenic. References: Blevins G et al. Oculoleptomeningeal amyloidosis in a large kindred with a new transthyretin variant Tyr69His. Neurology. 2003 May 27;60(10):1625-30. Schweitzer K et al. Oculoleptomeningeal amyloidosis in 3 individuals with the transthyretin variant Tyr69His. Can J Ophthalmol. 2009 Jun;44(3):317-9. Sekijima Y et al. The biological and chemical basis for tissue-selective amyloid disease. Cell. 2005 Apr 8;121(1):73-85. Ziskin JL et al. Neuropathologic analysis of Tyr69His TTR variant meningovascular amyloidosis with dementia. Acta Neuropathol Commun. 2015 Jul 10;3:43. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2022

The p.Y89H variant (also known as c.265T>C), located in coding exon 3 of the TTR gene, results from a T to C substitution at nucleotide position 265. The tyrosine at codon 89 is replaced by histidine, an amino acid with similar properties. This alteration has been detected in multiple individuals with transthyretin (TTR) amyloidosis, primarily TTR leptomeningeal/central nervous system amyloidosis (Schweitzer K et al. Can J Ophthalmol, 2009 Jun;44:317-9; Suhr OB et al. Amyloid, 2009 Dec;16:208-14; Ziskin JL et al. Acta Neuropathol Commun, 2015 Jul;3:43; Yamada Y et al. Amyloid, 2019 Dec;26:251-252; He S et al. Orphanet J Rare Dis, 2019 11;14:251). Experimental studies show that this alteration may impact protein function (Sekijima Y et al. Cell, 2005 Apr;121:73-85).This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	.;D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.8	.;D;.;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;D;.;.
Sift4G	Pathogenic	0.0	.;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.97, 0.98, 0.95
MutPred		0.95		Gain of disorder (P = 0.0296);Gain of disorder (P = 0.0296);Gain of disorder (P = 0.0296);Gain of disorder (P = 0.0296);
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs121918100; hg19: chr18-29175147;