rs121918086

Variant names:

• chr18-31595160-G-A
• rs121918086
• NM_000371.4:c.241G>A

Your query was ambiguous. Multiple possible variants found:

• chr18-31595160-G-A
• chr18-31595160-G-C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_000371.4(TTR):​c.241G>A​(p.Glu81Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 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. E81A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.88
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 32 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 chr18-31595161-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1791134.
• 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, 0.898
• PP5: Variant 18-31595160-G-A is Pathogenic according to our data. Variant chr18-31595160-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 13447.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4	c.241G>A	p.Glu81Lys	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.241G>A	p.Glu81Lys	missense_variant	Exon 3 of 4	1	NM_000371.4	ENSP00000237014.4
TTR	ENST00000649620.1	c.241G>A	p.Glu81Lys	missense_variant	Exon 5 of 6			ENSP00000497927.1
TTR	ENST00000610404.5	c.145G>A	p.Glu49Lys	missense_variant	Exon 3 of 4	5		ENSP00000477599.2
TTR	ENST00000541025.2	n.267G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1

Jan 30, 2019

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E81K variant (also known as c.241G>A), located in coding exon 3 of the TTR gene, results from a G to A substitution at nucleotide position 241. The glutamic acid at codon 81 is replaced by lysine, an amino acid with similar properties. This variant (also referred to as Glu61lys) has been reported in TTR amyloidosis cohorts and in individuals reported to have transthyretin amyloidosis characterized by later onset sensory-autonomic polyneuropathy and cardiomyopathy (Planté-Bordeneuve V et al. J. Med. Genet., 2003 Nov;40:e120; Noto Y et al. Amyloid, 2009;16:99-102; Hagenacker T et al. J. Neurol. Sci., 2014 Nov;346:331-2; Murakami T et al. J. Neurol. Sci., 2017 Oct;381:55-58; Nakano Y et al. J. Neurol. Sci., 2018 Jul;390:22-25). In addition, another variant affecting this codon (p.E81G, c.242A>G and referred to as Glu61Gly) has also been reported in an individual with transthyretin amyloidosis (Rosenzweig M et al. Amyloid, 2007 Mar;14:65-71). 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. -

Amyloidosis, hereditary systemic 1 Pathogenic:1

Aug 16, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	9.8
DANN	Benign	0.92
DEOGEN2	Uncertain	0.77	D;D;T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.83	.;T;T;T
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	-0.054	T
MutationAssessor	Benign	0.86	L;L;.;.
PhyloP100		1.9
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	.;N;.;.
REVEL	Uncertain	0.55
Sift	Benign	0.27	.;T;.;.
Sift4G	Benign	0.56	.;T;T;T
Polyphen		0.0070	B;B;.;.
Vest4		0.26, 0.34, 0.30
MutPred		0.71		Gain of methylation at E81 (P = 0.0119);Gain of methylation at E81 (P = 0.0119);Gain of methylation at E81 (P = 0.0119);Gain of methylation at E81 (P = 0.0119);
MVP		0.98
MPC		0.54
ClinPred		0.046	T
GERP RS		0.40
Varity_R		0.62
gMVP		0.91
Mutation Taster		=35/65	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: rs121918086; hg19: chr18-29175123;