rs121918096
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_000371.4(TTR):c.424_426delGTC(p.Val142del) variant causes a conservative inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000371.4 conservative_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTR | ENST00000237014.8 | c.424_426delGTC | p.Val142del | conservative_inframe_deletion | Exon 4 of 4 | 1 | NM_000371.4 | ENSP00000237014.4 | ||
TTR | ENST00000649620.1 | c.424_426delGTC | p.Val142del | conservative_inframe_deletion | Exon 6 of 6 | ENSP00000497927.1 | ||||
TTR | ENST00000610404.5 | c.328_330delGTC | p.Val110del | conservative_inframe_deletion | Exon 4 of 4 | 5 | ENSP00000477599.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Amyloidosis, hereditary systemic 1 Pathogenic:4
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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. -
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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. -
not provided Pathogenic:1
PP1, PP4, PM2_moderate, PM4, PS3_moderate, PS4 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at