rs774027595

Variant names:

• chr18-31598565-T-C
• rs774027595
• NM_000371.4:c.337-3T>C

Your query was ambiguous. Multiple possible variants found:

• chr18-31598565-T-C
• chr18-31598565-T-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_000371.4(TTR):​c.337-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: TTR NM_000371.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006734
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: -0.330
• Publications: 1 publications found

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]

TTR Gene-Disease associations (from GenCC):

• amyloidosis, hereditary systemic 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• familial amyloid neuropathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary ATTR amyloidosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• heart conduction disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• ATTRV122I amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000294516 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 18-31598565-T-C is Benign according to our data. Variant chr18-31598565-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229596.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS2: High AC in GnomAdExome4 at 44 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4	c.337-3T>C		splice_region_variant, intron_variant	Intron 3 of 3	ENST00000237014.8	NP_000362.1
LOC124904277	XR_007066326.1	n.129-2870A>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.337-3T>C		splice_region_variant, intron_variant	Intron 3 of 3	1	NM_000371.4	ENSP00000237014.4
TTR	ENST00000649620.1	c.337-3T>C		splice_region_variant, intron_variant	Intron 5 of 5			ENSP00000497927.1
TTR	ENST00000610404.5	c.241-3T>C		splice_region_variant, intron_variant	Intron 3 of 3	5		ENSP00000477599.2
ENSG00000294516	ENST00000724044.1	n.286-2870A>G		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251058 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461830 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1111994

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000189

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Nov 10, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

c.337-3T>C (intronic) in intron 3 of the TTR gene (NM_000371.3; chr18-29178528-T-C) SCICD Classification: variant of uncertain significance based on lack of case data. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Lab Classification (Invitae): variant of uncertain significance Gene-level evidence: TTR: There is enough evidence in the literature to associate the TTR gene with cardiovascular disease: TTR encodes transthyretin, a tetramer that circulates in the serum and cerebrospinal fluid to transport other molecules, such as thyroxine throughout the body. Pathogenic variants in TTR lead to amyloidosis, or aggregation and deposition of the transthyretin proteins into organs such as the heart. Amyloid deposition often leads to polyneuropathy and cardiomyopathy. TTR-amyloidosis is often a late-onset disorder. There are several common founder variants in TTR that lead to TTR-amyloidosis, some of which have genotype-phenotype correlations. Case data (not including our patient): 1 ClinVar: seen in one patient at the Laboratory for Molecular Medicine, classified as a VUS Cases in the literature: none reported This variant co-occurred with an LP variant in TTN in one of our patients with DCM. Segregation data: none reported Functional data: none reported Splice data (splice variants only): There is data that variants at the -3 position does not alter splicing patterns in most cases and is not highly conserved like canonical splice sites +/- 1 and 2 are (Buratti et al 2007). Conservation data: The thymine located at the third base of intron 3 is not conserved across species. Nearby pathogenic variants at this codon or neighboring codons: none Population data: Highest MAF in Latino population: 0.0029%. The variant was reported online in 3 of 138,410 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 2 of 63,214 individuals of European descent and 1 of 17,202 individuals of Latino descent (MAF=0.0029%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -

Feb 18, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Jan 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.337-3T>C variant in TTR has not been previously reported in individuals wi th cardiomyopathy, but has been identified in 2/66424 European chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs77 4027595). This variant is located in the 3' splice region. Computational tools d o not suggest an impact to splicing. However, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the c.337-3T>C variant is uncertain. -

Cardiovascular phenotype Uncertain:1

Mar 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.337-3T>C intronic variant results from a T to C substitution 3 nucleotides upstream from coding exon 4 in the TTR gene. This variant has been detected in an individual with cardiomyopathy (Skrahina V et al. Ann Med, 2021 Dec;53:1787-1796). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Amyloidosis, hereditary systemic 1 Uncertain:1

Jul 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 3 of the TTR gene. It does not directly change the encoded amino acid sequence of the TTR protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs774027595, gnomAD 0.003%). This variant has been observed in individual(s) with cardiomyopathy (PMID: 34658264). ClinVar contains an entry for this variant (Variation ID: 229596). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.6
DANN	Benign	0.55
PhyloP100		-0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000067
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs774027595; hg19: chr18-29178528;