rs267607161

Variant names:

• chr18-31598580-G-T
• rs267607161
• NM_000371.4:c.349G>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 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:10
• Conservation: PhyloP100: 5.94
• Publications: 64 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 19 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 18 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-G is described in ClinVar as Pathogenic. ClinVar VariationId is 13448.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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, 0.971
• PP5: Variant 18-31598580-G-T is Pathogenic according to our data. Variant chr18-31598580-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 13468.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.349G>T	p.Ala117Ser	missense_variant	Exon 4 of 4	ENST00000237014.8	NP_000362.1
LOC124904277	XR_007066326.1	n.129-2885C>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.349G>T	p.Ala117Ser	missense_variant	Exon 4 of 4	1	NM_000371.4	ENSP00000237014.4
TTR	ENST00000649620.1	c.349G>T	p.Ala117Ser	missense_variant	Exon 6 of 6			ENSP00000497927.1
TTR	ENST00000610404.5	c.253G>T	p.Ala85Ser	missense_variant	Exon 4 of 4	5		ENSP00000477599.2
ENSG00000294516	ENST00000724044.1	n.286-2885C>A		intron_variant	Intron 2 of 2

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

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251012 AF XY: 0.00000737

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 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

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:5

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

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Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4+PP4+PS3 -

Feb 14, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 10, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 18, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

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Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Feb 15, 2017

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 12, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3 -

Hyperthyroxinemia, dystransthyretinemic;C2751492:Amyloidosis, hereditary systemic 1;C5779776:Carpal tunnel syndrome 1 Pathogenic:1

May 11, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Dec 31, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 was reported in individual(s) with features consistent with hereditary transthyretin-related 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 variant in the Chinese-Taiwanese population based on presence in unrelated, affected individuals of this ethnic group (Liu YT et al. J. Neurol. Sci., 2008 Apr;267:91-9). An animal model expressing this variant exhibited phenotype(s) consistent with TTR-related disease (Kan HW et al. Neuropathol. Appl. Neurobiol., 2018 12;44:673-686). Other variant(s) at the same codon, p.A117G (c.350C>G), have been identified in individual(s) with features consistent with hereditary transthyretin-related 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 variant 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
LIST_S2	Benign	0.69	.;T;T;T
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;.;.
PhyloP100		5.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.7	.;N;.;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.012	.;D;.;.
Sift4G	Uncertain	0.049	.;D;D;D
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
Mutation Taster		=21/79	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: rs267607161; hg19: chr18-29178543;