Submissions for variant NM_001918.5(DBT):c.939G>C (p.Lys313Asn)

gnomAD frequency: 0.00001  dbSNP: rs398123676

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790732	SCV000232154	pathogenic	not provided	2013-09-04	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000179839	SCV000240048	pathogenic	Maple syrup urine disease	2013-01-01	criteria provided, single submitter	research
Counsyl	RCV000179839	SCV000791370	likely pathogenic	Maple syrup urine disease	2017-05-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000179839	SCV001410080	pathogenic	Maple syrup urine disease	2023-01-17	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with maple syrup urine disease (PMID: 18378174, 26257134). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 94017). This variant is present in population databases (rs398123676, gnomAD 0.01%). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 313 of the DBT protein (p.Lys313Asn). This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon.
Centogene AG - the Rare Disease Company	RCV001250158	SCV001424399	pathogenic	Maple syrup urine disease type 2		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000179839	SCV002033190	pathogenic	Maple syrup urine disease	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000179839	SCV004122501	pathogenic	Maple syrup urine disease	2023-10-04	criteria provided, single submitter	clinical testing	Variant summary: DBT c.939G>C (p.Lys313Asn) results in a non-conservative amino acid change located in the 2-oxoacid dehydrogenase acyltransferase, catalytic domain (IPR001078) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 5' splicing donor site and two predict the variant weakens the same canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251402 control chromosomes (gnomAD). c.939G>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Maple Syrup Urine Disease (Quental_2008, Gupta_2015, Cheema_2020, Strauss_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33083013, 26257134, 18378174, 31980395). Three ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001250158	SCV005442231	pathogenic	Maple syrup urine disease type 2	2024-12-19	criteria provided, single submitter	clinical testing