Submissions for variant NM_000481.4(AMT):c.471+2T>C

dbSNP: rs386833684

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000049645	SCV000636426	pathogenic	Glycine encephalopathy	2023-09-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 56233). Disruption of this splice site has been observed in individuals with nonketotic hyperglycinemia (PMID: 16450403). This variant is present in population databases (rs386833684, gnomAD 0.003%). This sequence change affects a donor splice site in intron 4 of the AMT gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AMT are known to be pathogenic (PMID: 16450403).
Illumina Laboratory Services, Illumina	RCV000049645	SCV001451514	pathogenic	Glycine encephalopathy	2020-06-26	criteria provided, single submitter	clinical testing	The AMT c.471+2T>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The variant has been reported in a compound heterozygous state in at least two unrelated families affected with the neonatal form of glycine encephalopathy (also known as nonketotic hyperglycinemia; NKH). The c.471+2T>C variant was found in trans with a missense variant in one family and with a frameshift variant in the second family (Kure et al. 2006). The c.471+2T>C variant was also identified in five individuals from a cohort of 578 families suspected to have classic NKH (Coughlin et al. 2016). Control data are unavailable for this variant which is found at a frequency of 0.000029 in the Latino population of the Genome Aggregation Database. This frequency is based on one allele in a region of good sequence coverage, so the variant is presumed to be rare. Based on the potential impact of slice donor variants, the variant's rarity and application of the ACMG criteria, the c.471+2T>C variant is classified as pathogenic for glycine encephalopathy.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000049645	SCV002103503	pathogenic	Glycine encephalopathy	2022-02-07	criteria provided, single submitter	clinical testing	Variant summary: AMT c.471+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251476 control chromosomes (gnomAD). c.471+2T>C has been reported in the literature in multiple compound heterozygous individuals affected with Glycine Encephalopathy (aka. Non-Ketotic Hyperglycinemia) (Kure_2006, Swanson_2015, Coughlin_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 , and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000049645	SCV004196852	pathogenic	Glycine encephalopathy	2023-03-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005025099	SCV005662591	pathogenic	Glycine encephalopathy 2	2024-02-08	criteria provided, single submitter	clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049645	SCV000082052	probable-pathogenic	Glycine encephalopathy		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Counsyl	RCV000049645	SCV000797065	pathogenic	Glycine encephalopathy	2018-01-10	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000049645	SCV001460427	pathogenic	Glycine encephalopathy	2020-09-16	no assertion criteria provided	clinical testing