Submissions for variant NM_003282.4(TNNI2):c.61G>A (p.Val21Met)

gnomAD frequency: 0.00019  dbSNP: rs200110633

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000266804	SCV000369683	uncertain significance	Arthrogryposis multiplex congenita	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000317217	SCV000369684	uncertain significance	Arthrogryposis multiplex congenita distal	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000994540	SCV000533337	likely benign	not provided	2022-09-07	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
CeGaT Center for Human Genetics Tuebingen	RCV000994540	SCV001148139	uncertain significance	not provided	2017-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002522192	SCV003679769	uncertain significance	Inborn genetic diseases	2021-08-13	criteria provided, single submitter	clinical testing	The c.61G>A (p.V21M) alteration is located in exon 5 (coding exon 4) of the TNNI2 gene. This alteration results from a G to A substitution at nucleotide position 61, causing the valine (V) at amino acid position 21 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000994540	SCV001550872	likely benign	not provided		no assertion criteria provided	clinical testing	The TNNI2 p.Val21Met variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs200110633) and in ClinVar (classified as a VUS by Illumina for Arthrogryposis Multiplex Congenita and Distal Arthrogryposis Multiplex Congenita, and as likely benign by GeneDx). The variant was also identified in control databases in 62 of 276310 chromosomes at a frequency of 0.000224 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 5 of 10172 chromosomes (freq: 0.000492), European (non-Finnish) in 53 of 125294 chromosomes (freq: 0.000423), Other in 2 of 7066 chromosomes (freq: 0.000283), European (Finnish) in 1 of 24506 chromosomes (freq: 0.000041) and South Asian in 1 of 30528 chromosomes (freq: 0.000033); it was not observed in the African, Latino or East Asian populations. The p.Val21 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and only two of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.