rs104894665

Positions:

• chr18-31593017-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000371.4(TTR):​c.191T>C​(p.Phe64Ser) 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. F64L) 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:3
• Conservation: PhyloP100: 6.11

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 16 ACMG points.

• PM1: In a strand (size 7) in uniprot entity TTHY_HUMAN there are 21 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 chr18-31593016-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• PP5: Variant 18-31593017-T-C is Pathogenic according to our data. Variant chr18-31593017-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31593017-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.191T>C	p.Phe64Ser	missense_variant	2/4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.191T>C	p.Phe64Ser	missense_variant	2/4	1	NM_000371.4	ENSP00000237014.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 03, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe64 amino acid residue in TTR. Other variant(s) that disrupt this residue have been observed in individuals with TTR-related conditions (PMID: 14627687), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TTR protein function. ClinVar contains an entry for this variant (Variation ID: 13461). This variant is also known as Phe44Ser. This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 9818883, 11812437, 11866053). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 64 of the TTR protein (p.Phe64Ser). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2002	- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2020

The p.F64S variant (also known as c.191T>C), located in coding exon 2 of the TTR gene, results from a T to C substitution at nucleotide position 191. The phenylalanine at codon 64 is replaced by serine, an amino acid with highly dissimilar properties. This alteration has been reported in several individuals with hereditary transthyretin amyloidosis (hATTR) (Klein CJ et al. Neurology, 1998 Nov;51:1462-4; Murakami A et al. Am. J. Ophthalmol., 2002 Feb;133:272-3). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Zanotti G et al. Eur. J. Biochem., 1995 Dec;234:563-9; Ambry internal data). A likely pathogenic alteration, p.F64Y, has been described in the same codon (Planté-Bordeneuve V et al. J Med Genet. 2003; 40(11):e120). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well 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	0.67
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;D;T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	.;T;T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.5	.;D;.;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0040	.;D;.;.
Sift4G	Uncertain	0.014	.;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.82, 0.82, 0.89
MutPred		0.72		Gain of disorder (P = 0.005);Gain of disorder (P = 0.005);Gain of disorder (P = 0.005);Gain of disorder (P = 0.005);
MVP		1.0
MPC		1.8
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.89
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: rs104894665; hg19: chr18-29172980;