rs121918096

Positions:

• chr18-31598651-TGTC-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000371.4(TTR):​c.424_426del​(p.Val142del) variant causes a inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TTR NM_000371.4 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.54

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]

LOC124904277 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 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
• PM4: Nonframeshift variant in NON repetitive region in NM_000371.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 18-31598651-TGTC-T is Pathogenic according to our data. Variant chr18-31598651-TGTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 13460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31598651-TGTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4	c.424_426del	p.Val142del	inframe_deletion	4/4	ENST00000237014.8	NP_000362.1
LOC124904277	XR_007066326.1	n.129-2959_129-2957del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.424_426del	p.Val142del	inframe_deletion	4/4	1	NM_000371.4	ENSP00000237014	P1
TTR	ENST00000610404.5	c.328_330del	p.Val110del	inframe_deletion	4/4	5		ENSP00000477599
TTR	ENST00000649620.1	c.424_426del	p.Val142del	inframe_deletion	6/6			ENSP00000497927	P1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 20, 2023	This variant, c.424_426del, results in the deletion of 1 amino acid(s) of the TTR protein (p.Val142del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 9191784, 11140845, 24101130). It has also been observed to segregate with disease in related individuals. This variant is also known as deltaV122. ClinVar contains an entry for this variant (Variation ID: 13460). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects TTR function (PMID: 15820680). This variant disrupts the p.Val142 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12050338, 15820680, 17503405, 18276611, 19781421, 22745357, 24184229, 25846356). 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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 02, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 16, 2016	Variant summary: The TTR c.424_426delGTC (p.Val142del) variant causes an in-frame deletion in the last exon. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals including a large family in which the variant segregates with disease (Munar-Ques_2001). The variant of interest has been classified as pathogenic/likely pathogenic by multiple reputable databases/clinical laboratories. Therefore, the variant of interest has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2000	- -

Computational scores

Source: dbNSFP v4.3

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: rs121918096; hg19: chr18-29178614;