Submissions for variant NM_024642.5(GALNT12):c.673A>T (p.Thr225Ser)

dbSNP: rs531023279

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000460711	SCV000561584	benign	not provided	2024-01-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000566214	SCV000673546	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-24	criteria provided, single submitter	clinical testing	The p.T225S variant (also known as c.673A>T), located in coding exon 3 of the GALNT12 gene, results from an A to T substitution at nucleotide position 673. The threonine at codon 225 is replaced by serine, an amino acid with similar properties. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.
PreventionGenetics, part of Exact Sciences	RCV003942564	SCV004766210	likely benign	GALNT12-related condition	2020-09-11	criteria provided, single submitter	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000460711	SCV001550379	likely benign	not provided		no assertion criteria provided	clinical testing	The GALNT12 p.Thr225Ser variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs531023279) and ClinVar (classified as benign by Invitae and as uncertain significance by Ambry Genetics). The variant was identified in control databases in 131 of 235946 chromosomes at a frequency of 0.0005552 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 126 of 26292 chromosomes (freq: 0.004792), Other in 3 of 6288 chromosomes (freq: 0.000477), African in 1 of 20938 chromosomes (freq: 0.000048) and European (non-Finnish) in 1 of 104262 chromosomes (freq: 0.00001), but was not observed in the Latino, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Thr225 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. 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. 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.