Submissions for variant NM_001267550.2(TTN):c.102275G>A (p.Arg34092His)

gnomAD frequency: 0.00004  dbSNP: rs757918924

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172163	SCV000051093	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000642952	SCV000764639	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-11-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 34092 of the TTN protein (p.Arg34092His). This variant is present in population databases (rs757918924, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 29961767). ClinVar contains an entry for this variant (Variation ID: 191822). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant is located in the M band of TTN (PMID: 25589632). Non-truncating variants in this region may be relevant for neuromuscular disorders, but have not been definitively shown to cause cardiomyopathy (PMID: 23975875). 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.
GeneDx	RCV000172163	SCV001825306	likely benign	not provided	2020-11-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390414	SCV002670515	uncertain significance	Cardiovascular phenotype	2019-05-29	criteria provided, single submitter	clinical testing	The p.R25027H variant (also known as c.75080G>A), located in coding exon 185 of the TTN gene, results from a G to A substitution at nucleotide position 75080. The arginine at codon 25027 is replaced by histidine, an amino acid with highly similar properties. This alteration (referred to as c.94570G>A, p.R31524H) has been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000172163	SCV003820264	uncertain significance	not provided	2022-04-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479042	SCV004223402	uncertain significance	not specified	2023-11-06	criteria provided, single submitter	clinical testing	Variant summary: TTN c.94571G>A (p.Arg31524His) results in a non-conservative amino acid change located in the M band region of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.7e-05 in 247456 control chromosomes (gnomAD). T c.94571G>A has been reported in the literature in individuals affected with dilated cardiomyopathy, however authors classifed this variant as VUS (examples: Hoorntje_2017, Minoche_2019). At-least one of these publications reported co-occurrence of other pathogenic variant (LMNA c.992G>A, p.Arg331Gln), supporting a benign role for this variant. These report(s) do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Type 2J. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28790152, 29961767). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classifed the variant as VUS (n=2) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172163	SCV001743156	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000172163	SCV001918869	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172163	SCV001932573	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000172163	SCV001953950	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172163	SCV001969089	uncertain significance	not provided		no assertion criteria provided	clinical testing