Submissions for variant NM_001267550.2(TTN):c.85115G>A (p.Gly28372Glu)

gnomAD frequency: 0.00006  dbSNP: rs190721759

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000461663	SCV000542652	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-11-17	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000184906	SCV000701307	uncertain significance	not provided	2018-08-16	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000184906	SCV001475041	uncertain significance	not provided	2020-03-03	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000184906	SCV001714632	uncertain significance	not provided	2021-03-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298512	SCV002598999	uncertain significance	not specified	2022-09-20	criteria provided, single submitter	clinical testing	Variant summary: TTN c.77411G>A (p.Gly25804Glu) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 248502 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in TTN causing Cardiomyopathy (0.00014 vs 0.00063), allowing no conclusion about variant significance. c.77411G>A has been reported in the literature in an individual affected with Preeclampsia (Gammill_2018). These report(s) 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. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002354506	SCV002651955	likely benign	Cardiovascular phenotype	2022-10-17	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.
Fulgent Genetics, Fulgent Genetics	RCV002500561	SCV002814098	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2021-09-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000184906	SCV003826669	uncertain significance	not provided	2020-12-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000184906	SCV000237662	not provided	not provided	2014-01-22	no assertion provided	clinical testing	Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in CARDIOMYOPATHY panel(s).