rs386134269

Variant names:

• chr18-31595127-A-C
• rs386134269
• NM_000371.4:c.208A>C

Your query was ambiguous. Multiple possible variants found:

• chr18-31595127-A-C
• chr18-31595127-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1 PM1 PM2 PM5 PP3 PP5_Moderate

The NM_000371.4(TTR):​c.208A>C​(p.Ser70Arg) 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 Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S70I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.55

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 13 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 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31595128-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825
• PP5: Variant 18-31595127-A-C is Pathogenic according to our data. Variant chr18-31595127-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36889.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-31595127-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4	c.208A>C	p.Ser70Arg	missense_variant	Exon 3 of 4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.208A>C	p.Ser70Arg	missense_variant	Exon 3 of 4	1	NM_000371.4	ENSP00000237014.4
TTR	ENST00000649620.1	c.208A>C	p.Ser70Arg	missense_variant	Exon 5 of 6			ENSP00000497927.1
TTR	ENST00000610404.5	c.112A>C	p.Ser38Arg	missense_variant	Exon 3 of 4	5		ENSP00000477599.2
TTR	ENST00000541025.2	n.234A>C		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:1

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;T;.
Eigen	Benign	0.098
Eigen_PC	Benign	0.027
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.86	.;D;D;T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.1	M;M;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.9	.;N;.;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0090	.;D;.;.
Sift4G	Uncertain	0.025	.;D;T;D
Polyphen		0.95	P;P;.;.
Vest4		0.52, 0.61, 0.96
MutPred		0.66		Loss of glycosylation at S70 (P = 0.0143);Loss of glycosylation at S70 (P = 0.0143);Loss of glycosylation at S70 (P = 0.0143);Loss of glycosylation at S70 (P = 0.0143);
MVP		1.0
MPC		0.90
ClinPred		0.90	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.76
gMVP		0.94

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: rs386134269; hg19: chr18-29175090;