ClinVar Miner

Submissions for variant NM_000229.2(LCAT):c.491G>A (p.Arg164His)

gnomAD frequency: 0.00001  dbSNP: rs769485083
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001975068 SCV002240892 pathogenic not provided 2024-01-17 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 164 of the LCAT protein (p.Arg164His). This variant is present in population databases (rs769485083, gnomAD 0.003%). This missense change has been observed in individual(s) with high-density lipoprotein (HDL) deficiency and/or lecithin cholesterol acyltransferase (LCAT) deficiency (PMID: 7607641, 28870971, 30333156). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg140His. ClinVar contains an entry for this variant (Variation ID: 1458807). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LCAT protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects LCAT function (PMID: 7607641). This variant disrupts the p.Arg164 amino acid residue in LCAT. Other variant(s) that disrupt this residue have been observed in individuals with LCAT-related conditions (PMID: 24174160), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001975068 SCV005325133 likely pathogenic not provided 2023-07-11 criteria provided, single submitter clinical testing Published functional studies demonstrate a loss of enzyme activity when p.(R164H) was expressed in COS-7 cells (Steyrer et al., 1995); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as R140H; This variant is associated with the following publications: (PMID: 16216249, 28870971, 34256778, 34789074, 7607641, 30333156)

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