Submissions for variant NM_004211.5(SLC6A5):c.1472A>G (p.Tyr491Cys)

gnomAD frequency: 0.00004  dbSNP: rs121908494

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000006119	SCV003515886	uncertain significance	Hyperekplexia 3	2022-08-08	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 491 of the SLC6A5 protein (p.Tyr491Cys). This variant is present in population databases (rs121908494, gnomAD 0.003%). This missense change has been observed in individual(s) with hyperekplexia (PMID: 16751771). ClinVar contains an entry for this variant (Variation ID: 5763). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SLC6A5 function (PMID: 16751771). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000006119	SCV005398118	likely pathogenic	Hyperekplexia 3	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with hyperekplexia 3 (MIM#614618). (I) 0108 - This gene is associated with both recessive and dominant disease. Recessive disease is caused by biallelic loss of function variants, where both truncating and missense variants have been reported. Missense variants with a dominant negative mechanism have been reported to cause dominant disease however, this is rare (PMID: 16751771). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2, v3) <0.01 for a recessive condition (5 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated sodium neurotransmitter symporter family domain (PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an individual. This variant has been reported as pathogenic, and observed in a single compound heterozygous patient with hyperekplexia (ClinVar, PMID: 16751771). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected HEK293 cells and Xenopus oocytes demonstrated that this variant causes impaired glycine uptake and currents could not be induced (PMID: 16751771). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000006119	SCV000026301	pathogenic	Hyperekplexia 3	2006-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000006119	SCV000054571	pathologic	Hyperekplexia 3	2012-10-04	no assertion criteria provided	curation	Converted during submission to Pathogenic.