Submissions for variant NM_001267550.2(TTN):c.96904+1G>A

dbSNP: rs1553517092

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001377466	SCV001574803	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-04-26	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 347 of the TTN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is found in the A-band of this gene. While this particular variant has not been reported in the literature, truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632). ClinVar contains an entry for this variant (Variation ID: 202384). For these reasons, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002367860	SCV002664407	uncertain significance	Cardiovascular phenotype	2022-06-06	criteria provided, single submitter	clinical testing	The c.69709+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 174 of the TTN gene. Exon 174 is located in the A-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This alteration disrupts the canonical splice site and is expected to cause aberrant splicing. However, although direct evidence is unavailable, this alteration is predicted to result in an in-frame transcript that is not expected to trigger nonsense-mediated mRNA decay. The exact functional effect of the predicted splice impact is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003994008	SCV004813369	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-02-14	criteria provided, single submitter	clinical testing	Variant summary: TTN c.89200+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 222060 control chromosomes. To our knowledge, no occurrence of c.89200+1G>A in individuals affected with Limb-Girdle Muscular Dystrophy, Type 2J and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 466674). Based on the evidence outlined above, the variant was classified as likely pathogenic.