rs121918089

chr18-31598610-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_000371.4(TTR):c.379A>G(p.Ile127Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. I127M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 4.01

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]

LOC124904277 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 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 chr18-31598612-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1073325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 18-31598610-A-G is Pathogenic according to our data. Variant chr18-31598610-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31598610-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTR	NM_000371.4	c.379A>G	p.Ile127Val	missense_variant	4/4	ENST00000237014.8
LOC124904277	XR_007066326.1	n.129-2915T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000237014.8	c.379A>G	p.Ile127Val	missense_variant	4/4	1	NM_000371.4	P1
TTR	ENST00000649620.1	c.379A>G	p.Ile127Val	missense_variant	6/6			P1
TTR	ENST00000610404.5	c.283A>G	p.Ile95Val	missense_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	TTR: PM2, PM5, PS3:Moderate, PS4:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 21, 2023	This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) In some published literature, this variant is referred to as p.Ile107Val. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2022	Published functional studies demonstrate that TTR dimers from individuals heterozygous for TTRI127V are less stable than dimers from wild type individuals (Atland K et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as I107V; This variant is associated with the following publications: (PMID: 22301727, 8081397, 30306720, 20209591, 22745357, 19781421, 12039669, 7914929, 24101130, 32723050, 33481097, 33188503, 33844361, 34668655, 34602081, 34746851, 33283548, 34391735, 35665045, 35599006, 35417510, 35346209, 35331287, ScirpaR2022, 17443043, 9748014, 27025994, 27066555, 34658264, 26537620, 29520877, 26656838, 34440326, 35637921, 35580748, 17503405) -

Familial amyloid neuropathy Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 26, 2016	Variant summary: The TTR c.379A>G variant affects a conserved nucleotide, resulting in amino acid change from Ile to Val. 3/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). However, functional studies indicate that TTRI107V dimers and tetramers decreased stability compared to controls. This variant is not found in 121416 control chromosomes, but has been cited in numerous ATTR patients from various ethnicities. Taken together, this is a disease variant and was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 13, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 127 of the TTR protein (p.Ile127Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with amyloidosis (PMID: 7914929, 8081397, 9748014, 20209591, 24101130, 26537620, 27025994, 27066555). This variant is also known as p.Ile107Val. ClinVar contains an entry for this variant (Variation ID: 13450). 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%. Experimental studies have shown that this missense change affects TTR function (PMID: 17503405). This variant disrupts the p.Ile127 amino acid residue in TTR. Other variant(s) that disrupt this residue have been observed in individuals with TTR-related conditions (PMID: 22745357, 24480837), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

not specified Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 01, 2017

- -

Hereditary amyloidosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Feb 22, 2022

ACMG classification criteria: PS3 strong, PS4 strong, PM2 moderated -

Hyperthyroxinemia, dystransthyretinemic;C2751492:Familial amyloid neuropathy;C5779776:Carpal tunnel syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 09, 2021

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2023

The c.379A>G (p.I127V) alteration is located in exon 4 (coding exon 4) of the TTR gene. This alteration results from a A to G substitution at nucleotide position 379, causing the isoleucine (I) at amino acid position 127 to be replaced by a valine (V). Based on data from the Genome Aggregation Database (gnomAD), the TTR c.379A>G alteration was not observed with coverage at this location. This variant, historically known as p.I107V, has been detected in multiple individuals with TTR-related amyloidosis (Jacobson, 1994; Planté-Bordeneuve, 1998; Damy, 2016; Kuzume, 2016). Two different alterations located at the same amino acid position, p.I127F (c.379A>T, historically known as p.I107F) and p.I127M (c.381T>G, historically known as p.I107M), have also been detected in individuals with TTR-related amyloidosis (Cappellari, 2011; Lv, 2014). This amino acid is highly conserved in available vertebrate species. Functional studies indicate that this variant results in unstable interaction between transthyretin tetramers (Altland, 2007). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Benign	15
Dann	Benign	0.47
DEOGEN2	Uncertain	0.61	D;D;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.50	D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.36	T
Polyphen		0.013	B;B;.
Vest4		0.40, 0.74
MutPred		0.64		Gain of glycosylation at S132 (P = 0.0885);Gain of glycosylation at S132 (P = 0.0885);.;
MVP		0.94
MPC		0.40
ClinPred		0.50	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.88

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: rs121918089; hg19: chr18-29178573;