18-31595230-T-G

Variant names:

• chr18-31595230-T-G
• rs121918072
• NM_000371.4:c.311T>G

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.311T>G​(p.Ile104Ser) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I104L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.20
• Publications: 15 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 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 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 chr18-31595229-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 808384.
• 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, 0.814
• PP5: Variant 18-31595230-T-G is Pathogenic according to our data. Variant chr18-31595230-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 13423.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.311T>G	p.Ile104Ser	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.311T>G	p.Ile104Ser	missense_variant	Exon 3 of 4	1	NM_000371.4	ENSP00000237014.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:2

May 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 104 of the TTR protein (p.Ile104Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Indiana/Swiss hereditary Amyloidosis (FAP II) (PMID: 2840822, 3760189, 9547003, 23713495, 25997029). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13423). 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 with a positive predictive value of 95%. This variant disrupts the p.Ile104 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1350083, 9701270). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Feb 27, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Oct 09, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TTR c.311T>G; p.Ile104Ser variant (rs121918072), also known as Ile84Ser, is reported in the literature in multiple individuals affected with TTR amyloidosis (Altland 2007. Dwulet 1986, Fontana 2015, Zeldenrust 2012) and co-segregated with disease in at least four individuals in one family (Dwulet 1986). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The isoleucine at codon 104 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.600). However, functional studies demonstrate instability of the variant tetramer protein (Altland 2007). Further, other amino acid substitutions at this codon (p.Ile104Asn, p.Ile104Thr) have been reported in individuals with TTR amyloidosis and also exhibit altered multimerization (Altland 2007). Based on available information, the p.Ile104Ser 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. Dwulet FE and Benson MD. Characterization of a transthyretin (prealbumin) variant associated with familial amyloidotic polyneuropathy type II (Indiana/Swiss). J Clin Invest. 1986 Oct;78(4):880-6. 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. Zeldenrust SR. Genotype--phenotype correlation in FAP. Amyloid. 2012 Jun;19 Suppl 1:22-4. -

Cardiovascular phenotype Pathogenic:1

Jun 02, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I104S pathogenic mutation (also known as c.311T>G and I84S), located in coding exon 3 of the TTR gene, results from a T to G substitution at nucleotide position 311. The isoleucine at codon 104 is replaced by serine, an amino acid with dissimilar properties. This mutation has been reported in multiple individuals with familial amyloid polyneuropathy (Dwulet FE et al. J. Clin. Invest., 1986 Oct;78:880-6; Zeldenrust SR. Amyloid, 2012 Jun;19 Suppl 1:22-4; Ihse E et al. Amyloid, 2013 Sep;20:142-50; Fontana M et al. Radiology, 2015 Nov;277:388-97; Wallace MR et al. Am. J. Hum. Genet., 1988 Aug;43:182-7). In a functional study, the authors demonstrated that TTR monomers with this mutation are in an unfolded state 90% of the time in 2.5M urea (Altland K et al. Electrophoresis, 2007 Jun;28:2053-64). In addition, at least one likely pathogenic variant, p.I104T, has been described in the same codon (Stangou et al Transplantation 1998 Jul 27;66(2):229-33). 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	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	22
DANN	Benign	0.86
DEOGEN2	Uncertain	0.77	D;D;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.029
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	.;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.8	L;L;.;.
PhyloP100		4.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.5	.;N;.;.
REVEL	Uncertain	0.60
Sift	Benign	0.61	.;T;.;.
Sift4G	Benign	0.43	.;T;T;T
Polyphen		0.23	B;B;.;.
Vest4		0.47, 0.54, 0.68
MutPred		0.69		Gain of disorder (P = 9e-04);Gain of disorder (P = 9e-04);Gain of disorder (P = 9e-04);Gain of disorder (P = 9e-04);
MVP		1.0
MPC		0.74
ClinPred		0.46	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.67
gMVP		0.94
Mutation Taster		=5/95	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: rs121918072; hg19: chr18-29175193;