ClinVar Miner

Submissions for variant NM_000371.3(TTR):c.368G>A (p.Arg123His) (rs148538950)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159431 SCV000209377 uncertain significance not provided 2016-06-08 criteria provided, single submitter clinical testing The R123H variant in the TTR gene has not been published as a disease-causing mutation but another missense change at the same residue, R123S (aka R103S based on alternate nomenclature), has been reported in association with cardiomyopathy (Connors L et al., 2000). Nevertheless, the NHLBI Exome Sequencing Project has identified R123H in 3/4,406 alleles from individuals of African American ancestry, suggesting it may be a rare benign variant in this population. In addition, numerous non-amyloid variants in nearby residues (G121S, P122R, R124C, R124H) have been reported (Sekijima et al., 2012), indicating this region of the TTR protein may be tolerant of change. Moreover, a missense variant in the neighboring residue, R124H, was suspected to suppress amyloid formation (protective effect) when present in trans with the common amylodogenic mutation V50M (reported as R104H/V30M using alternate nomenclature) (Terazaki H et al., 1999). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Invitae RCV000457018 SCV000541950 uncertain significance Amyloidogenic transthyretin amyloidosis 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 123 of the TTR protein (p.Arg123His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs148538950, ExAC 0.04%). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 26537620). ClinVar contains an entry for this variant (Variation ID: 181698). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845370 SCV000987428 uncertain significance Primary familial hypertrophic cardiomyopathy criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000159431 SCV001151527 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000457018 SCV001284994 uncertain significance Amyloidogenic transthyretin amyloidosis 2017-04-28 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Molecular Genetics Laboratory,London Health Sciences Centre RCV001173301 SCV001336385 uncertain significance Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing

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