Submissions for variant NM_001235.5(SERPINH1):c.188C>T (p.Ala63Val)

gnomAD frequency: 0.00038  dbSNP: rs576480194

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000886184	SCV001029674	likely benign	not provided	2023-11-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000886184	SCV001946088	benign	not provided	2020-07-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30986427)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002279610	SCV002565024	likely benign	Osteogenesis imperfecta	2020-08-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702504	SCV005202741	likely benign	not specified	2024-07-10	criteria provided, single submitter	clinical testing	Variant summary: SERPINH1 c.188C>T (p.Ala63Val) results in a non-conservative amino acid change located in the Serpin domain (IPR023796) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 246024 control chromosomes, predominantly at a frequency of 0.0048 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in SERPINH1 causing Osteogenesis Imperfecta Type 10 phenotype c.188C>T has been reported in an unknown zygosity in the literature in at least two individuals affected with osteogenesis imperfecta (e.g., Lin_2024). However, these report(s) do not provide unequivocal conclusions about association of the variant with Osteogenesis Imperfecta Type 10. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 37270749). ClinVar contains an entry for this variant (Variation ID: 713953). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003975581	SCV004788303	likely benign	SERPINH1-related disorder	2020-08-28	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).