ClinVar Miner

Submissions for variant NM_000155.4(GALT):c.1030C>A (p.Gln344Lys) (rs111033814)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000224058 SCV000110051 pathogenic not provided 2017-07-07 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224058 SCV000281630 pathogenic not provided 2014-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000224058 SCV000521168 likely pathogenic not provided 2016-12-27 criteria provided, single submitter clinical testing The Q344K missense change has been reported in patients with the severe galactosemia phenotype (Berry et al. 2000; Berry et al. 2004). The Q344K variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q344K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (E340K, L342I, A345D) have been reported in the Human Gene Mutation Database in association with galactosemia (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we interpret Q344K to be likely pathogenic.
Invitae RCV000022266 SCV000835443 uncertain significance Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2018-06-29 criteria provided, single submitter clinical testing This sequence change replaces glutamine with lysine at codon 344 of the GALT protein (p.Gln344Lys). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another GALT variant in individuals affected with galactosemia (PMID: 11397328, 11754113). ClinVar contains an entry for this variant (Variation ID: 25320). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000022266 SCV000885501 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2018-07-06 criteria provided, single submitter clinical testing The GALT c.1030C>A; p.Gln344Lys variant (rs111033814) has been reported in patients diagnosed with hereditary galactosemia (Elsas 1998, Berry 2000, Yang 2001). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 25320) and observed on only 2 alleles in the Genome Aggregation Database. The highly conserved glutamine at codon 344 is located at the subunit interface and is predicted to be important for maintaining inter-subunit hydrogen bonds and stabilize the enzyme complex (Facchiano 2010). Functional characterization indicates that, when found in trans with another pathogenic GALT variant, the p.Gln344Lys variant abrogates GALT activity in erythrocytes (Berry 2000). Based on available information, this variant is considered pathogenic. References: Berry G et al. Galactose breath testing distinguishes variant and severe galactose-1-phosphate uridyltransferase genotypes. Pediatr Res. 2000; 48(3):323-8. Elsas LJ et al. The molecular biology of galactosemia. Genet Med. 1998; 1(1):40-8. Facchiano A et al. Analysis of galactosemia-linked mutations of GALT enzyme using a computational biology approach. Protein Eng Des Sel. 2010; 23(2):103-13. Yang Y et al. Molecular analysis in newborns from Texas affected with galactosemia. Hum Mutat. 2002; 19(1):82-3.
Baylor Genetics RCV000022266 SCV001163254 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV000022266 SCV000042951 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2012-12-04 no assertion criteria provided clinical testing Converted during submission to Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000022266 SCV000052460 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2015-06-12 no assertion criteria provided clinical testing
Counsyl RCV000022266 SCV000793554 likely pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2019-06-26 no assertion criteria provided clinical testing

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