Submissions for variant NM_004407.4(DMP1):c.815G>A (p.Arg272His)

gnomAD frequency: 0.00202  dbSNP: rs145237146

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000764554	SCV000451505	uncertain significance	Hypophosphatemic rickets, autosomal recessive, 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Eurofins Ntd Llc (ga)	RCV000591260	SCV000705349	uncertain significance	not provided	2017-01-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764554	SCV000895642	uncertain significance	Hypophosphatemic rickets, autosomal recessive, 1	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000591260	SCV001117423	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000591260	SCV004152950	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	DMP1: BP4, BS2
PreventionGenetics, part of Exact Sciences	RCV003902356	SCV004724166	likely benign	DMP1-related condition	2022-10-18	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000591260	SCV001551624	likely benign	not provided		no assertion criteria provided	clinical testing	The DMP1 p.Arg272His variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs145237146) and ClinVar (classified as uncertain significance by Illumina, EGL Genetic Diagnostics and Fulgent Genetics, and as benign by Invitae). The variant was identified in control databases in 531 of 281746 chromosomes (1 homozygous) at a frequency of 0.001885 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 145 of 35372 chromosomes (freq: 0.004099), Other in 21 of 7198 chromosomes (freq: 0.002917), European (non-Finnish) in 330 of 128426 chromosomes (freq: 0.00257), Ashkenazi Jewish in 14 of 10324 chromosomes (freq: 0.001356), African in 8 of 24814 chromosomes (freq: 0.000322), South Asian in 9 of 30580 chromosomes (freq: 0.000294), European (Finnish) in 3 of 25114 chromosomes (freq: 0.00012), and East Asian in 1 of 19918 chromosomes (freq: 0.00005). The p.Arg272 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.