Submissions for variant NM_001267550.2(TTN):c.12547A>G (p.Lys4183Glu)

gnomAD frequency: 0.00010  dbSNP: rs201565932

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213210	SCV000272863	uncertain significance	not specified	2015-04-04	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Lys3945Glu va riant in TTN has not been previously reported in individuals with cardiomyopathy , but has been identified in 16/66676 European chromosomes by the Exome Aggregat ion Consortium (http://exac.broadinstitute.org; dbSNP rs201565932). Computationa l prediction tools and conservation analyses do not provide strong support for o r against an impact to the protein. In summary, while the clinical significance of the p.Lys3945Glu variant is uncertain, these data suggest that it is more lik ely to be benign.
GeneDx	RCV001697191	SCV000718022	likely benign	not provided	2021-02-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000643855	SCV000765542	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002450638	SCV002617881	likely benign	Cardiovascular phenotype	2019-08-22	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.
CeGaT Center for Human Genetics Tuebingen	RCV001697191	SCV004148152	uncertain significance	not provided	2023-01-01	criteria provided, single submitter	clinical testing	TTN: PM2, BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000213210	SCV005203406	uncertain significance	not specified	2025-01-30	criteria provided, single submitter	clinical testing	Variant summary: TTN c.10361-2326A>G is located at a position not widely known to affect splicing. This variant corresponds to c.12547A>G, p.Lys4183Glu in NM_001267550. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0001 in 248470 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.0001 vs 0.00039), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.10361-2326A>G in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 229594). Based on the evidence outlined above, the variant was classified as uncertain significance.