rs730881169

chr18-31593020-C-Achr18-31593020-C-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.194C>A(p.Ala65Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A65V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.33

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr18-31593019-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 850453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 18-31593020-C-A is Pathogenic according to our data. Variant chr18-31593020-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31593020-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTR	NM_000371.4	c.194C>A	p.Ala65Asp	missense_variant	2/4	ENST00000237014.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000237014.8	c.194C>A	p.Ala65Asp	missense_variant	2/4	1	NM_000371.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	May 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2012	This mutation is denoted Ala65Asp (aka A65D) at the protein level and c.194 C>A at the cDNA level. A heterozygous C>A nucleotide substitution in exon 2 of the TTR gene results in the replacement of an Alanine codon (GCC) with an Aspartic acid codon (GAC) at amino acid position 65 in transthyretin. The Ala65Asp (aka Ala45Asp, using alternative nomenclature) mutation in the TTR gene has been reported previously in association with cardiac amyloidosis (Saraiva M et al., 1995). The Ala65Asp mutation results in a non-conservative amino acid substitution of a non-polar Alanine residue with a polar Aspartic acid residue. Additionally, the NHLBI ESP Exome Variant Server reports Ala65Asp was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Furthermore, mutations in this codon (Ala65Ser, Ala65Thr) and in nearby codons (Phe64Leu, Phe64Ser, Phe64Tyr, Gly67Ala) have been reported in association with amyloidosis, further supporting the functional importance of this region of the protein. The variant is found in HCM panel(s). -

Familial amyloid neuropathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 01, 2019

This variant has been observed in individuals affected with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 7599630, 23713495, 24953234). This variant is also known as A45D in the literature. ClinVar contains an entry for this variant (Variation ID: 181702). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with aspartic acid at codon 65 of the TTR protein (p.Ala65Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala65 amino acid residue in TTR. Other variant(s) that disrupt this residue have been observed in individuals with TTR-related conditions (PMID: 28460244, 1570831, 10842718), which suggests that this may be a clinically significant amino acid residue. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;T;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	M;M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
Polyphen		1.0	D;D;.;.
Vest4		0.72, 0.76, 0.74
MutPred		0.77		Gain of disorder (P = 0.0619);Gain of disorder (P = 0.0619);Gain of disorder (P = 0.0619);Gain of disorder (P = 0.0619);
MVP		1.0
MPC		1.7
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		1.0

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: rs730881169; hg19: chr18-29172983;