Submissions for variant NM_032581.4(HYCC1):c.191A>G (p.Tyr64Cys)

gnomAD frequency: 0.00105  dbSNP: rs146913158

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000870519	SCV001012022	benign	Hypomyelination and Congenital Cataract	2025-01-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001171984	SCV001334907	uncertain significance	not provided	2024-06-01	criteria provided, single submitter	clinical testing	HYCC1: PP3
GeneDx	RCV001171984	SCV001811213	likely benign	not provided	2020-12-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001171984	SCV002542272	uncertain significance	not provided	2021-07-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356064	SCV001551124	benign	not specified		no assertion criteria provided	clinical testing	The FAM126A p.Tyr64Cys variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs146913158) and in control databases in 326 of 282290 chromosomes (2 homozygous) at a frequency of 0.001155 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: European (non-Finnish) in 282 of 128792 chromosomes (freq: 0.00219), South Asian in 17 of 30604 chromosomes (freq: 0.000556), African in 12 of 24966 chromosomes (freq: 0.000481), Other in 3 of 7208 chromosomes (freq: 0.000416), European (Finnish) in 10 of 25112 chromosomes (freq: 0.000398) and Latino in 2 of 35336 chromosomes (freq: 0.000057), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Tyr64 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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, this variant meets our laboratory's criteria to be classified as benign.
PreventionGenetics, part of Exact Sciences	RCV003920390	SCV004736832	likely benign	HYCC1-related disorder	2023-02-16	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).