Submissions for variant NM_001267550.2(TTN):c.90991C>T (p.Pro30331Ser)

gnomAD frequency: 0.00030  dbSNP: rs75022916

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000728236	SCV000237739	likely benign	not provided	2020-10-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25589632)
Ambry Genetics	RCV000618251	SCV000735460	likely benign	Cardiovascular phenotype	2020-09-08	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.
Invitae	RCV000697121	SCV000825715	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-06-20	criteria provided, single submitter	clinical testing	This sequence change replaces proline with serine at codon 30331 of the TTN protein (p.Pro30331Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs75022916, ExAC 0.07%). This variant has not been reported in the literature in individuals with TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 202973). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are unavailable for the TTN gene. This variant identified in the TTN gene is located in the A band of the resulting protein (PMID: 25589632). It is unclear how this variant impacts the function of this protein. 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.
Eurofins Ntd Llc (ga)	RCV000728236	SCV000855782	uncertain significance	not provided	2017-07-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000184964	SCV001360678	uncertain significance	not specified	2019-11-25	criteria provided, single submitter	clinical testing	Variant summary: TTN c.83287C>T (p.Pro27763Ser) results in a non-conservative amino acid change located in the A-band of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 248746 control chromosomes, predominantly at a frequency of 0.00065 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Cardiomyopathy (4.4e-05 vs 0.00063), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.83287C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions (evaluation after 2014) cite the variant three times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000728236	SCV003824230	uncertain significance	not provided	2023-12-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003390909	SCV004111252	uncertain significance	TTN-related condition	2023-08-09	criteria provided, single submitter	clinical testing	The TTN c.90991C>T variant is predicted to result in the amino acid substitution p.Pro30331Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.070% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179416636-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.