rs121918098

chr18-31592939-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000371.4(TTR):c.113A>G(p.Asp38Gly) variant causes a missense change. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. D38E) 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:3
• Conservation: PhyloP100: 7.09

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 18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain 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 chr18-31592940-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 1359774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 18-31592939-A-G is Pathogenic according to our data. Variant chr18-31592939-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 13463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31592939-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTR	NM_000371.4	c.113A>G	p.Asp38Gly	missense_variant	2/4	ENST00000237014.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000237014.8	c.113A>G	p.Asp38Gly	missense_variant	2/4	1	NM_000371.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial amyloid neuropathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 01, 2012	The Asp38Gly variant (TTR) has been identified in 4 individuals with leptomening eal/CNS-related TTR amyloidosis, including one individual with restrictive cardi omyopathy (note, the variant is also referred to as Asp18Gly; Vidal 1996, Jin 20 04, Barreiros 2010). In addition, this variant segregates with disease in 4 affe cted family members, including one obligate carrier, and was absent from 80 cont rol chromosomes (Vidal 1996, Jin 2004). Furthermore, functional analyses showed the Asp38Gly variant results in an abnormal protein that is highly destabilized, has diminished secretion, and has abnormal cellular localization (Hammarstrom 2 003, Sekijima 2005). In summary, the Asp38Gly variant is highly likely to be pat hogenic based upon correlation with clinical phenotype, segregation with disease , and functional studies. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 25, 2021	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp38 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23126592, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. This variant has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 8579098, 20209591). It has also been observed to segregate with disease in related individuals. This variant is also known as D18G. ClinVar contains an entry for this variant (Variation ID: 13463). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with glycine at codon 38 of the TTR protein (p.Asp38Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. -

AMYLOIDOSIS, LEPTOMENINGEAL, TRANSTHYRETIN-RELATED Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;T;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;H;.;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.53	T
Polyphen		1.0	D;D;.;.
Vest4		0.95, 0.96, 0.91
MutPred		0.97		Gain of methylation at K35 (P = 0.0418);Gain of methylation at K35 (P = 0.0418);Gain of methylation at K35 (P = 0.0418);Gain of methylation at K35 (P = 0.0418);
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121918098; hg19: chr18-29172902;