ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.504G>C (p.Gln168His)

gnomAD frequency: 0.00002  dbSNP: rs747771347
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235521 SCV000294040 uncertain significance not provided 2016-03-16 criteria provided, single submitter clinical testing The Q168H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved in mammals. The Q168H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV002519832 SCV003514447 uncertain significance Charcot-Marie-Tooth disease type 2 2024-07-26 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 168 of the LMNA protein (p.Gln168His). This variant is present in population databases (rs747771347, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 246472). 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 expected to disrupt LMNA protein function with a positive predictive value of 95%. 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.

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