rs267607161

Positions:

• chr18-31598580-G-T

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.349G>T​(p.Ala117Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,172 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. A117G) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.94

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 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 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 chr18-31598581-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2057055.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 18-31598580-G-T is Pathogenic according to our data. Variant chr18-31598580-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31598580-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTR	NM_000371.4	c.349G>T	p.Ala117Ser	missense_variant	4/4	ENST00000237014.8
LOC124904277	XR_007066326.1	n.129-2885C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000237014.8	c.349G>T	p.Ala117Ser	missense_variant	4/4	1	NM_000371.4	P1
TTR	ENST00000649620.1	c.349G>T	p.Ala117Ser	missense_variant	6/6			P1
TTR	ENST00000610404.5	c.253G>T	p.Ala85Ser	missense_variant	4/4	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251012 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135706

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial amyloid neuropathy Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 14, 2017	Variant summary: The TTR c.349G>T (p.Ala117Ser) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 splice prediction tools predict no significant impact on normal splicing, however, 3/5 tools predict that this variant may remove a cryptic 3' splicing acceptor site. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant has been reported in multiple ATTR patients in Chinese population and is absent in 121750 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 117 of the TTR protein (p.Ala117Ser). This variant is present in population databases (rs267607161, gnomAD 0.01%). This missense change has been observed in individuals with transthyretin amyloidosis (PMID: 10611950, 18022643, 20697105, 22412233, 23713495). This variant is also known as Ala97Ser. ClinVar contains an entry for this variant (Variation ID: 13468). 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: 20697105). This variant disrupts the p.Ala117 (also known as p.Ala97) amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8133316, 10611950, 14986482, 20209591). 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 10, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 18, 2010	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 15, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	-	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. This variant has been previously reported in multiple families with amyloidosis. The variant was first reported by Tachibana et al (1999) in a cohort of Chinese patients with familial amyloid polyneuropathy (FAP). Unfortunately only the abstract is available and this does not list segregation, functional, or control data. Lachmann et al (2000) briefly reported this variant in a family in which two brothers with progressive peripheral and autonomic neuropathy as well as subclinical cardiac and renal amyloid deposition. The variant was observed in two Chinese-Taiwanese brothers who presented with amyloidosis at ages 56 and 60. Liu et al (2008) reported the variant in five unrelated Chinese-Taiwanese patients between the ages of 55 and 67 with amyloidosis. The phenotype included late-onset polyneuropathy, carpel tunnel syndrome, autonomic dysfunction, and cardiac involvement. Interestingly, haplotype analysis was inconsistent with a founder effect. Yang et al (2010) observed the variant in 19 unrelated Taiwanese patients with polyneuropathy between the ages of 48 and 68. Another variant at the same codon has also been reported in association with amyloidosis: p.Ala97Gly (Yasude et al 1994). In silico analysis with Polyphen2 predicts the variant to be possibly damaging. The Alanine at codon 97 is completely conserved as are the neighboring residues. Lachmann et al (2000) reported the variant was absent in at least 50 control individuals. Liu et al (2008) did not observe it in 100 Chinese control individuals. Yang et al (2010) reported the variant was not seen in their sample of 365 Taiwanese controls, for a total of 515 control individuals. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 11, 2022

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2021

The p.A117S pathogenic mutation (also known as c.349G>T and A97S) located in coding exon 4 of the TTR gene, results from a G to T substitution at nucleotide position 349. The alanine at codon 117 is replaced by serine, an amino acid with similar properties. This variant has been reported in multiple individuals with TTR amyloidosis (Tachibana N et al. Amyloid, 1999 Dec;6:282-8; Yang NC et al. Neurology, 2010 Aug;75:532-8; Hsu HC et al. BMC Neurol, 2017 Sep;17:178; Chen Q et al. Mol. Neurobiol., 2018 Jun;55:4911-4917; Yuan Z et al. J Clin Neurosci, 2019 Feb;60:164-166; Chao HC et al. Ann Clin Transl Neurol, 2019 May;6:913-922; Liao CH et al. Diagnostics (Basel), 2019 Apr;9:). This variant was proposed as a hot spot in the Chinese-Taiwanese population based on 5 unrelated individuals of this ethnic group with familial TTR and a clinical picture including carpal tunnel syndrome, late-onset polyneuropathy, and autonomic dysfunction with cardiac involvement (Liu YT et al. J. Neurol. Sci., 2008 Apr;267:91-9). Mouse heterozygous knock-in models demonstrated consistent neuropathy phenotype and amyloid deposits confirmed by anti-TTR immunohistochemistry (Kan HW et al. Neuropathol. Appl. Neurobiol., 2018 12;44:673-686). A disease-causing mutation, p.A117G, has been described in the same codon in individuals with TTR amyloidosis (Barreiros AP et al. Liver Transpl., 2010 Mar;16:314-23; Koike H et al. J. Neurol. Sci., 2018 Nov;394:99-106). 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	0.38	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M;M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
Polyphen		0.99	D;D;.;.
Vest4		0.68, 0.76, 0.84
MutPred		0.82		Gain of glycosylation at A117 (P = 0.0152);Gain of glycosylation at A117 (P = 0.0152);Gain of glycosylation at A117 (P = 0.0152);.;
MVP		1.0
MPC		1.3
ClinPred		0.95	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.94

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: rs267607161; hg19: chr18-29178543;