Submissions for variant NM_001267550.2(TTN):c.81899G>A (p.Arg27300His)

gnomAD frequency: 0.00040  dbSNP: rs55850344

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040674	SCV000064365	likely benign	not specified	2013-03-06	criteria provided, single submitter	clinical testing	Arg24732His in exon 275 of TTN: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, multiple mammals (guinea pig, hedgehog, elephant, rock hyrax, and platypus) have a histidine (His) at this position, despite high nearby amino acid conserv ation. In addition, computational analyses (biochemical properties, AlignGVGD, a nd PolyPhen2) do not suggest a high likelihood of impact to the protein. This va riant has been identified in 5/8226 European American chromosomes from a broad p opulation by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EV S/; dbSNP rs55850344).
GeneDx	RCV000176835	SCV000237620	likely benign	not provided	2020-10-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27930701, 28255936, 17344846)
Invitae	RCV000227596	SCV000286856	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-10-17	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000176835	SCV000333425	uncertain significance	not provided	2016-06-07	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415094	SCV000492653	uncertain significance	Myopathy	2014-12-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000176835	SCV000608994	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	TTN: BP4
Ambry Genetics	RCV000619262	SCV000735249	likely benign	Cardiovascular phenotype	2020-06-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768910	SCV000900283	benign	Cardiomyopathy	2023-06-16	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000176835	SCV001714637	uncertain significance	not provided	2022-10-21	criteria provided, single submitter	clinical testing	BP4
Athena Diagnostics Inc	RCV000040674	SCV001879709	likely benign	not specified	2021-01-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040674	SCV002766501	uncertain significance	not specified	2023-09-11	criteria provided, single submitter	clinical testing	Variant summary: TTN c.74195G>A (p.Arg24732His) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 247888 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Cardiomyopathy (0.00037 vs 0.00063), allowing no conclusion about variant significance. c.74195G>A has been reported in the literature in individuals who suffered a sudden unexplained cardiac death (e.g. Campuzano_2015, Campuzano_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. 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: 26516846, 28255936). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS or likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.