ClinVar Miner

Submissions for variant NM_005518.4(HMGCS2):c.830T>A (p.Ile277Asn)

gnomAD frequency: 0.00002  dbSNP: rs775637086
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001097608 SCV001253903 uncertain significance 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx RCV001593264 SCV001826426 uncertain significance not provided 2019-04-19 criteria provided, single submitter clinical testing The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV001097608 SCV002180290 uncertain significance 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2021-10-12 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with asparagine at codon 277 of the HMGCS2 protein (p.Ile277Asn). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is present in population databases (rs775637086, ExAC 0.03%). This variant has not been reported in the literature in individuals affected with HMGCS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 874559). 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 C15"). 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.
Ambry Genetics RCV003283976 SCV003972613 uncertain significance Inborn genetic diseases 2023-06-06 criteria provided, single submitter clinical testing The c.830T>A (p.I277N) alteration is located in exon 4 (coding exon 4) of the HMGCS2 gene. This alteration results from a T to A substitution at nucleotide position 830, causing the isoleucine (I) at amino acid position 277 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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