rs1555631417

Positions:

• chr18-31595221-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_000371.4(TTR):​c.302C>T​(p.Ala101Val) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A101T) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4
• Conservation: PhyloP100: -0.534

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a helix (size 6) in uniprot entity TTHY_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr18-31595220-G-A is described in Lovd as [Pathogenic].
• PP5: Variant 18-31595221-C-T is Pathogenic according to our data. Variant chr18-31595221-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 495842.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=5, Pathogenic=1}. Variant chr18-31595221-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4	c.302C>T	p.Ala101Val	missense_variant	3/4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.302C>T	p.Ala101Val	missense_variant	3/4	1	NM_000371.4	ENSP00000237014	P1
TTR	ENST00000649620.1	c.302C>T	p.Ala101Val	missense_variant	5/6			ENSP00000497927	P1
TTR	ENST00000610404.5	c.206C>T	p.Ala69Val	missense_variant	3/4	5		ENSP00000477599
TTR	ENST00000541025.2	n.328C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2022	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 A81V; This variant is associated with the following publications: (PMID: Holcman_2021_Abstract, 17554795, 25044787, 32789836, 30328212, 34024775) -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 09, 2017	Variant summary: c.302C>T affects a non-conserved nucleotide, resulting in amino acid change from Ala to Val. 3/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant was not found in 121370 control chromosomes. The variant of interest was reported in at least 1 kindred presented with cardiac amyloidosis (Benson_2007) with limited information on segregation. This variant has not, to our knowledge, been evaluated for functional impact by in vivo/vitro studies by the time of evaluation. Another alteration of the same codon, p.A101T, have been reported in association with cardiac amyloidosis. It is possible that this variant is pathogenic, however, more clinical and segregation date needed to classify this variant with confidence. Taken together, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 28, 2023	The TTR c.302C>T; p.Ala101Val variant (rs1555631417), also known as Ala81Val in the mature protein, is reported in the literature in several individuals affected with transthyretin-related amyloidosis (Benson 2007, Chen 2021, Gawor 2022). This variant is also reported in ClinVar (Variation ID: 495842). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other variants at this codon (c.301G>A; p.Ala101Thr) have been reported in individuals with transthyretin-related amyloidosis (Connors 2003), but clinical significance is uncertain. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.752). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. References: Benson MD et al. The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve. 2007 Oct;36(4):411-23. PMID: 17554795. Chen Z et al. Hereditary Transthyretin Amyloidosis- Clinical and Genetic Characteristics of a Multiracial South-East Asian Cohort in Singapore. J Neuromuscul Dis. 2021;8(4):723-733. PMID: 34024775. Connors LH et al. Tabulation of human transthyretin (TTR) variants, 2003. Amyloid. 2003 Sep;10(3):160-84. PMID: 14640030. Gawor M et al. Spectrum of transthyretin gene mutations and clinical characteristics of Polish patients with cardiac transthyretin amyloidosis. Cardiol J. 2022;29(6):985-993. PMID: 32789836. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2023

The p.A101V variant (also known as c.302C>T), located in coding exon 3 of the TTR gene, results from a C to T substitution at nucleotide position 302. The alanine at codon 101 is replaced by valine, an amino acid with similar properties. This variant, which is also known as p.A81V, has been reported in individuals with transthyretin (TTR) amyloidosis, including cardiomyopathy and polyneuropathy (Benson MD et al. Muscle Nerve, 2007 Oct;36:411-23; Rowczenio D et al. Hum Mutat, 2019 Jan;40:90-96; Tseng H et al. Acta Cardiol Sin, 2021 Sep;37:549-553; Gawor M et al. Cardiol J, 2022 Aug;29:985-993; Sha Q et al. ESC Heart Fail, 2023 Oct;[ePub ahead of print]). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is poorly conserved in available vertebrate species. 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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 08, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 101 of the TTR protein (p.Ala101Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 25044787, 32789836, 34024775). This variant is also known as Ala81Val. ClinVar contains an entry for this variant (Variation ID: 495842). 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%. This variant disrupts the p.Ala101 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Feb 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	8.4
DANN	Benign	0.93
DEOGEN2	Pathogenic	0.88	D;D;T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.68	.;T;T;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Uncertain	-0.052	T
MutationAssessor	Uncertain	2.5	M;M;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.0	.;N;.;.
REVEL	Uncertain	0.57
Sift	Benign	0.082	.;T;.;.
Sift4G	Benign	0.28	.;T;T;T
Polyphen		0.0020	B;B;.;.
Vest4		0.27, 0.45, 0.70
MutPred		0.51		Gain of methylation at K100 (P = 0.0446);Gain of methylation at K100 (P = 0.0446);Gain of methylation at K100 (P = 0.0446);Gain of methylation at K100 (P = 0.0446);
MVP		0.94
MPC		0.47
ClinPred		0.077	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1555631417; hg19: chr18-29175184;