rs1555631390

chr18-31595128-G-GTGAGTC

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4 PP5

The NM_000371.4(TTR):c.212_217dup(p.Glu71_Ser72dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR NM_000371.4 inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.0170

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 hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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.
• PP5: Variant 18-31595128-G-GTGAGTC is Pathogenic according to our data. Variant chr18-31595128-G-GTGAGTC is described in ClinVar as [Pathogenic]. Clinvar id is 545518.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTR	NM_000371.4	c.212_217dup	p.Glu71_Ser72dup	inframe_insertion	3/4	ENST00000237014.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000237014.8	c.212_217dup	p.Glu71_Ser72dup	inframe_insertion	3/4	1	NM_000371.4	P1
TTR	ENST00000610404.5	c.116_121dup	p.Glu39_Ser40dup	inframe_insertion	3/4	5
TTR	ENST00000649620.1	c.212_217dup	p.Glu71_Ser72dup	inframe_insertion	5/6			P1
TTR	ENST00000541025.2	n.238_243dup		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial amyloid neuropathy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Amyloidosis Center, Boston University School of Medicine

Mar 16, 2018

A 37 year old African American man presented with sensorimotor polyneuropathy, and myopathy in his lower extremities. Deposits of variant TTR were detected in the right shin skin using tandem mass spectrometry. A fat aspirate was Congo red positive for amyloid deposits, the patient's brother was also diagnosed with amyloidosis by sural nerve biopsy. Following nine months of diflunisal treatment (250mg/daily), the patient demonstrated progression of sensorimotor polyneuropathy, and also autonomic neuropathy. Diflunisal treatment was stopped due to lack of efficacy. The patient was found to have a six base pair duplication in TTR exon 3 (c.212_217dupAGTCTG) by DNA sequencing of the TTR gene. The patient died from recurrent aspiration pneumonia, debilitating peripheral and autonomic neuropathy. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555631390; hg19: chr18-29175091;