Submissions for variant NM_001378969.1(KCND3):c.1573A>G (p.Met525Val)

gnomAD frequency: 0.00076  dbSNP: rs145890206

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000619982	SCV000737986	likely benign	Cardiovascular phenotype	2018-10-03	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.
Athena Diagnostics	RCV001289014	SCV001476505	benign	not specified	2020-01-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001429957	SCV001632679	likely benign	Spinocerebellar ataxia type 19/22	2024-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV001354553	SCV001772713	likely benign	not provided	2021-03-27	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354553	SCV001549199	uncertain significance	not provided		no assertion criteria provided	clinical testing	The KCND3 p.Met525Val variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs145890206) and ClinVar (classified as likely benign by Ambry Genetics). The variant was also identified in control databases in 64 of 282736 chromosomes at a frequency of 0.000226 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 60 of 24962 chromosomes (freq: 0.002404), Latino in 2 of 35440 chromosomes (freq: 0.000056) and European (non-Finnish) in 2 of 129060 chromosomes (freq: 0.000016), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other, and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Met525 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004547759	SCV004795625	likely benign	KCND3-related disorder	2021-11-18	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).