rs121918083

Positions:

• chr18-31592914-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000371.4(TTR):​c.88T>C​(p.Cys30Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,960 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., 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:6 U:1
• Conservation: PhyloP100: 4.49

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a chain Transthyretin (size 126) in uniprot entity TTHY_HUMAN there are 141 pathogenic changes around while only 6 benign (96%) in NM_000371.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant 18-31592914-T-C is Pathogenic according to our data. Variant chr18-31592914-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13444.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=2, Likely_pathogenic=2}. Variant chr18-31592914-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4	c.88T>C	p.Cys30Arg	missense_variant	2/4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.88T>C	p.Cys30Arg	missense_variant	2/4	1	NM_000371.4	ENSP00000237014.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461720 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727168

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 AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 05, 2016	Variant Summary: The c.88T>C variant involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a pathogenic outcome. The variant, also known as Cys10Arg, involves the only free Cysteine in TTR and is hypothesized to cause structural changes in the heterozygous TTR dimer and tetramer that lead to polymerization of TTR molecules (Uemichi_1992). The variant is absent from the large, broad ExAC control population. The variant was found in multiple affected individuals in the literature, including a family in which all tested affected males carried the variant while three unaffected females also carried the variant, suggesting some role of sex in the occurrence of disease (Uemichi_1992). One clinical lab has classified the variant as "pathogenic". Therefore, taken together, this variant has been classified as Likely Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1992	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 30 of the TTR protein (p.Cys30Arg). This variant is present in population databases (rs121918083, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 1362222, 24664531; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as Cys10Arg. ClinVar contains an entry for this variant (Variation ID: 13444). 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%. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 28, 2024	The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with clinical features associated with autosomal dominant hereditary transthyretin-related amyloidosis. This variant has been identified in at least one family with clinical features associated with this gene, where incomplete penetrance was noted (PMID: 1362222). In some published literature, this variant is referred to as p.Cys10Arg. Computational tools predict that this variant is damaging. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

The p.C30R variant (also known as c.88T>C), located in coding exon 2 of the TTR gene, results from a T to C substitution at nucleotide position 88. The cysteine at codon 30 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration, which is also known as p.C10R, has been reported in transthyretin (TTR) amyloidosis and related cardiomyopathy cohorts; however, clinical details were limited (Uemichi T et al. J Med Genet, 1992 Dec;29:888-91; Suhr OB et al. Transplantation, 2016 Feb;100:373-81; Ungerer MN et al. Amyloid, 2021 Jun;28:91-99). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;D;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.80	.;T;T;T
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.1	.;D;.;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0070	.;D;.;.
Sift4G	Uncertain	0.016	.;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.89, 0.90, 0.94
MutPred		0.74		Gain of disorder (P = 0.0116);Gain of disorder (P = 0.0116);Gain of disorder (P = 0.0116);Gain of disorder (P = 0.0116);
MVP		0.98
MPC		1.8
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
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: rs121918083; hg19: chr18-29172877;