ClinVar Miner

Submissions for variant NM_003482.4(KMT2D):c.15536G>A (p.Arg5179His)

dbSNP: rs267607237
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000723481 SCV000230781 pathogenic not provided 2014-08-18 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000007972 SCV000781686 likely pathogenic Kabuki syndrome 1 2016-11-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001043636 SCV001207392 pathogenic Kabuki syndrome 2024-03-22 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 5179 of the KMT2D protein (p.Arg5179His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Kabuki syndrome (PMID: 20711175, 23913813, 25755104, 27302555). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7536). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KMT2D protein function. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000007972 SCV004171249 pathogenic Kabuki syndrome 1 2023-11-30 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000007972 SCV005400514 pathogenic Kabuki syndrome 1 2024-10-10 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Kabuki syndrome 1 (MIM#147920) and branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (MIM#620186). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMIDs: 21882399, 31949313). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v4) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0600 - Variant is located in the annotated FYRN family domain (DECIPHER). (I) 0702 - Other variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Three alternate amino acid changes have been observed in unrelated individuals diagnosed with Kabuki syndrome: (p.Arg5179Cys), (p.Arg5179Leu), and (p.Arg5179Pro). Each variant has been reported in ClinVar as pathogenic or likely pathogenic. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Clinical laboratories in ClinVar have reported this variant as pathogenic four times, and likely pathogenic once. This variant has been seen in multiple unrelated individuals diagnosed with Kabuki syndrome (PMIDs: 20711175, 37043208). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed)(by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx RCV000723481 SCV005848246 pathogenic not provided 2024-08-13 criteria provided, single submitter clinical testing 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; This variant is associated with the following publications: (PMID: 25755104, 20711175, 27302555, 28475860, 21671394, 28404210, 23913813, 30459467, 32368696, 28991257, 36891680, 37043208, 31941532, 37010288, 35904121)
OMIM RCV000007972 SCV000028177 pathogenic Kabuki syndrome 1 2010-09-01 no assertion criteria provided literature only
Autoinflammatory diseases unit, CHU de Montpellier RCV000007972 SCV001438151 pathogenic Kabuki syndrome 1 2015-05-27 no assertion criteria provided clinical testing

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