Submissions for variant NM_000191.3(HMGCL):c.825C>G (p.Asn275Lys)

dbSNP: rs1287973337

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672781	SCV000797921	uncertain significance	Deficiency of hydroxymethylglutaryl-CoA lyase	2018-02-14	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000672781	SCV004048325	likely pathogenic	Deficiency of hydroxymethylglutaryl-CoA lyase		criteria provided, single submitter	clinical testing	The HMGCL (c.825C>G) (p.Asn275Lys) variant has been reported as one of the double heterozygous (c.109G>T (p.Glu37*) variant in an individual affected with HMG-CoA lyase deficiency (Puisac B et. al., 2013). The p.Asn275Lys variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It has been submitted to ClinVar with as Variant of Uncertain Significance (VUS) but no details are available for independent assessment. The amino acid Asn at position 275 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be probably damaging by PolyPhen 2 and deleterious by SIFT. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another reportable variant the molecular diagnosis is not confirmed.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800528	SCV005422179	uncertain significance	not specified	2024-10-23	criteria provided, single submitter	clinical testing	Variant summary: HMGCL c.825C>G (p.Asn275Lys) results in a non-conservative amino acid change located in the Pyruvate carboxyltransferase domain (IPR000891) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.825C>G has been reported in the literature in at-least one individual affected with HMG-CoA Lyase Deficiency (example, Puisac_2013). These data do not allow any conclusion about variant significance. 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: 23465862). ClinVar contains an entry for this variant (Variation ID: 556736). Based on the evidence outlined above, the variant was classified as uncertain significance.