18-31592974-G-C

Position:

• chr18-31592974-G-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1 PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000371.4(TTR):​c.148G>C​(p.Val50Leu) 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 Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V50A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.83

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 20 ACMG points.

• PS1: Transcript NM_000371.4 (TTR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a strand (size 6) in uniprot entity TTHY_HUMAN there are 17 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 chr18-31592975-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911
• PP5: Variant 18-31592974-G-C is Pathogenic according to our data. Variant chr18-31592974-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 13440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31592974-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4	c.148G>C	p.Val50Leu	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.148G>C	p.Val50Leu	missense_variant	2/4	1	NM_000371.4	ENSP00000237014	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 05, 2021	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Val50 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1544214, 22620962, 23523753, 23833285, 24555660, 26521788). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 13440). This variant is also known as Val30Leu. This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 1520326). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 50 of the TTR protein (p.Val50Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1998	- -

Charcot-Marie-Tooth disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2019

The p.V50L pathogenic mutation (also known as c.148G>C and V30L), located in coding exon 2 of the TTR gene, results from a G to C substitution at nucleotide position 148. The valine at codon 50 is replaced by leucine, an amino acid with highly similar properties.The p.V50L mutation (c.148G>C and c.148G>T) has been reported in multiple individuals with TTR amyloidosis (Utsugisawa K et al. Muscle Nerve, 1998 Dec;21:1783-5; Mitsuhashi S et al. Amyloid, 2005 Dec;12:216-25; Suhr OB et al. Amyloid, 2009 Dec;16:208-14; Nakagawa M et al. Amyloid, 2013 Jun;20:138-40), and was identified in two distant affected relatives in a large family with incomplete penetrance (Chen H et al. Sci Rep, 2016 05;6:26362). This variant was not reported in the gnomAD database, with coverage at this position. A disease-causing mutation, p.V50M, has been described in the same codon (Soares ML et al. Eur. J. Hum. Genet., 2004 Mar;12:225-377). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	16
DANN	Benign	0.54
DEOGEN2	Uncertain	0.67	D;D;T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.87	.;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.9	L;L;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.80	.;N;.;.
REVEL	Uncertain	0.56
Sift	Benign	0.69	.;T;.;.
Sift4G	Benign	0.34	.;T;T;T
Polyphen		0.065	B;B;.;.
Vest4		0.67, 0.80, 0.93
MutPred		0.79		Loss of MoRF binding (P = 0.1547);Loss of MoRF binding (P = 0.1547);Loss of MoRF binding (P = 0.1547);Loss of MoRF binding (P = 0.1547);
MVP		0.98
MPC		0.52
ClinPred		0.27	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.97

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: rs28933979; hg19: chr18-29172937;