Submissions for variant NM_000371.4(TTR):c.416C>T (p.Thr139Met)

gnomAD frequency: 0.00177  dbSNP: rs28933981

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036376	SCV000060029	benign	not specified	2021-09-15	criteria provided, single submitter	clinical testing	The p.Thr139Met variant in TTR is classified as benign because it has been identified in 0.3% (351/129156) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Additionally, this variant has been reported in both unaffected individuals as well as in individuals with asymptomatic euthyroid hyperthyroxinemia (Scrimshaw 1992, Alves 1997). Functional and clinical studies indicate that this variant may provide protective benefit against TTR amyloidosis by improving protein stability and reducing the propensity to form amyloidogenic aggregates (Quintas 1997, Almeida 2000, Hammarstrom 2001, Costa 2008, Palhano 2009, Borgault 2011). ACMG/AMP Criteria applied: BA1.
GeneDx	RCV000036376	SCV000169669	benign	not specified	2013-05-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000990084	SCV000554851	benign	Amyloidosis, hereditary systemic 1	2024-01-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000714134	SCV000605506	benign	not provided	2023-11-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618448	SCV000735097	likely benign	Cardiovascular phenotype	2018-05-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Athena Diagnostics	RCV000036376	SCV000844811	benign	not specified	2020-12-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000990084	SCV001140875	likely benign	Amyloidosis, hereditary systemic 1	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000714134	SCV001151528	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	TTR: BS1
Illumina Laboratory Services, Illumina	RCV000990084	SCV001284998	benign	Amyloidosis, hereditary systemic 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170385	SCV001332962	benign	Cardiomyopathy	2018-06-21	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001173303	SCV001336387	likely benign	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV003993656	SCV004809208	likely pathogenic	Hyperthyroxinemia, dystransthyretinemic	2023-09-01	criteria provided, single submitter	clinical testing	PS3,PS4_Moderate,PP4
OMIM	RCV000014376	SCV000034625	risk factor	AMYLOIDOSIS, HEREDITARY SYSTEMIC 1, MODIFIER OF	2001-09-28	no assertion criteria provided	literature only
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000714134	SCV001969591	likely benign	not provided		no assertion criteria provided	clinical testing