Submissions for variant NM_001756.4(SERPINA6):c.344T>A (p.Leu115His)

gnomAD frequency: 0.00236  dbSNP: rs113418909

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479165	SCV000565553	likely pathogenic	not provided	2024-04-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with reduced cortisol binding affinity (PMID: 1504007); Observed in the homozygous state or with an additional SERPINA6 variant in patients with decreased cortisol-binding activity, but has not been described in association with frank CBG deficiency (PMID: 1504007, 7061486); Also known as L93H and CBG Leuven using alternate nomenclature; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7061486, 1504007, 8212073, 22013108, 25010111, 30409984, 34308089, 27113851, 36681594)
CeGaT Center for Human Genetics Tuebingen	RCV000479165	SCV001246282	uncertain significance	not provided	2019-10-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689423	SCV005184912	likely benign	not specified	2024-05-10	criteria provided, single submitter	clinical testing	Variant summary: SERPINA6 c.344T>A (p.Leu115His) results in a non-conservative amino acid change located in the Serpin domain (IPR023796) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 251354 control chromosomes, predominantly at a frequency of 0.0033 within the Non-Finnish European subpopulation in the gnomAD database, strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.344T>A has been reported in the literature in one individual affected with multiple diseases including diabetes mellitus, coronary artery disease, hypertension, osteoarthritis, gastric erosions secondary to the use of nonsteroidal anti-inflammatory drugs, septic shock and acute respiratory failure (Smith_1992). These report(s) do not provide unequivocal conclusions about association of the variant with Corticosteroid-Binding Globulin Deficiency. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal steroid binding capacity in Chinese hamster ovary cells (Smith_1992). The following publication has been ascertained in the context of this evaluation (PMID: 1504007). ClinVar contains an entry for this variant (Variation ID: 16974). Based on the evidence outlined above, the variant was classified as likely benign.
OMIM	RCV000018495	SCV000038777	pathogenic	Corticosteroid-binding globulin deficiency	1993-06-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003934839	SCV004750771	uncertain significance	SERPINA6-related disorder	2023-12-07	no assertion criteria provided	clinical testing	The SERPINA6 c.344T>A variant is predicted to result in the amino acid substitution p.Leu115His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.34% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.