ClinVar Miner

Submissions for variant NM_000371.3(TTR):c.424G>A (p.Val142Ile) (rs76992529)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 14
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000078674 SCV000605508 pathogenic not provided 2017-06-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000243161 SCV000318173 pathogenic Cardiovascular phenotype 2017-11-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Other strong data supporting pathogenic classification
Athena Diagnostics Inc RCV000078674 SCV000616219 pathogenic not provided 2015-08-19 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000211747 SCV000902011 pathogenic Cardiomyopathy 2017-09-07 criteria provided, single submitter clinical testing
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000735409 SCV000854564 pathogenic Anemia; Pancytopenia; Pneumonia; Bone marrow hypocellularity criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078674 SCV000331406 pathogenic not provided 2013-05-10 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515257 SCV000611333 pathogenic Carpal tunnel syndrome; Dystransthyretinemic euthyroidal hyperthyroxinemia; Amyloidogenic transthyretin amyloidosis 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000078674 SCV000209380 pathogenic not provided 2018-11-28 criteria provided, single submitter clinical testing The V142I variant in the TTR gene, also reported as V122I due to the use of alternative nomenclature, is a common amyloidogenic TTR pathogenic variant in the African-American population, seen in approximately 3-4% of individuals (Jacobson et al., 1990; Jacobson et al., 1997a; Jacobson et al., 1997b; Yamashita et al., 2005). Allele frequency data from a more recent study by Jacobson et al. (2016) was consistent with V142I originating in a small number of founder carriers in southern West Africa. Additionally, the V142I variant has been reported in individuals of varying ethnic backgrounds in the Online Registry for Mutations in Hereditary Amyloidosis. V142I has been reported in patients with familial amyloid cardiomyopathy and senile systemic amyloidosis (SSA) who were heterozygous or homozygous for V142I (Jacobson et al., 1990; Jacobson et al., 1997a; Jacobson et al., 1997b). These disorders usually have an age-dependent penetrance with onset later in life (age > 50-60 years), characterized by amyloid deposits in the heart leading to congestive heart failure and conduction system disturbances (Jacobson et al., 1997a; Jacobson et al., 1997b). Peripheral and autonomic neuropathy are absent or less evident in individuals with this pathogenic variant (Sekijima et al., 2012).Functional studies by Jiang et al. (2001) demonstrated V142I renders the TTR complex unstable, leading to unfolding and lower tetramer stability. Askanas et al. (2003) demonstrated that cultured skeletal muscle fibers from patients harboring the V142I variant had vacuolar degeneration, congophilic inclusions, clusters of immunocolocalizing beta-amyloid and TTR accumulations. Another variant affecting the same residue (V142A) has been reported in association with cardiac amyloidosis and peripheral neuropathy (Connors et al., 2003; Stenson et al., 2014). In addition, V142I has been observed in multiple other unrelated individuals who have been referred for genetic testing of cardiomyopathy at GeneDx.
Gharavi Laboratory,Columbia University RCV000078674 SCV000809425 pathogenic not provided 2018-09-16 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000014368 SCV000408397 pathogenic Amyloidogenic transthyretin amyloidosis 2016-06-14 criteria provided, single submitter clinical testing The c.424G>A (p.Val142Ile) variant, also known as p.Val122Ile, has been described as the most common pathogenic variant in familial transthyretin amyloidosis patients and is known to present in a heterozygous state at a frequency of 3.5% in the African American population (Sekijima et al. 2012; Jacobsen et al. 2015). The variant is associated with an exclusively cardiac phenotype, a severe restrictive cardiomyopathy with absence of significant neurological involvement. Prior to age 60 the variant does not appear to affect mortality or cardiac function. However, after age 60, the carriers of the variant demonstrated earlier onset of disease with an increased risk for mortality and congestive heart failure (Buxbaum et al. 2010; Reddi et al. 2014; Quarta et al. 2015; Damy et al. 2016). Across a selection of the available literature, the p.Val142Ile variant has been identified in a homozygous state in 19 patients, in a compound heterozygous state in two patients, and in a heterozygous state in 36 patients (Jacobsen et al. 1990; Jacobson et al. 1997; Buxbaum et al. 2010; Givens et al. 2013; Reddi et al. 2014; Dubrey et al. 2014; Carr et al. 2015; Quarta et al. 2015; Damy et al. 2016; Cappelli et al. 2016). The p.Val142Ile variant was absent from 43 control alleles but is reported at a frequency of 0.02778 in the Yoruba in Ibadan, Nigeria, population of the 1000 Genomes Project. This allele frequency is high but is consistent with the disease prevalence. Functional studies showed that the variant demonstrated an altered speed of tetramer dissociation, greater formation of amyloid fibrils, and an unstable TTR tetramer compared to wild type (Jiang et al. 2001; Steward et al. 2008). Based on the collective evidence, the p.Val142Ile variant is classified as pathogenic for familial transthyretin amyloidosis.
Integrated Genetics/Laboratory Corporation of America RCV000030575 SCV000053250 pathogenic Amyloid Cardiomyopathy, Transthyretin-related 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Invitae RCV000014368 SCV000284750 pathogenic Amyloidogenic transthyretin amyloidosis 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 142 of the TTR protein (p.Val142Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs76992529, ExAC 1.5%). This variant has been observed in individuals with transthyretin amyloidosis (PMID: 25846356, 24184229, 12050338, 19781421, 22745357). This variant is a common cause of amyloidosis in individuals of African American ancestry and is present in 3.5% of this population (PMID: 20435197, 22877808). It has also been observed in individuals of other ethnic backgrounds (PMID: 25846356, 22745357). This variant is also known as p.Val122Ile in the literature. ClinVar contains an entry for this variant (Variation ID: 14063). This variant has been reported to affect TTR protein function (PMID: 17503405, 18276611, 15820680). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000014368 SCV000060031 not provided Amyloidogenic transthyretin amyloidosis 2018-09-14 no assertion provided clinical testing
OMIM RCV000014368 SCV000034617 pathogenic Amyloidogenic transthyretin amyloidosis 2003-07-22 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.